Fibroblast growth factor receptor-like molecules and uses thereof

ABSTRACT

The present invention provides Fibroblast Growth Factor Receptor-Like (FGFR-L) polypeptides and nucleic acid molecules encoding the same. The invention also provides selective binding agents, vectors, host cells, and methods for producing FGFR-L polypeptides. The invention further provides pharmaceutical compositions and methods for the diagnosis, treatment, amelioration, and/or prevention of diseases, disorders, and conditions associated with FGFR-L polypeptides.

[0001] This application is a continuation of U.S. Provisional Patent Application No. 60/191,379, filed on Mar. 22, 2000, the disclosure of which is explicitly incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention relates to Fibroblast Growth Factor Receptor-Like (FGFR-L) polypeptides and nucleic acid molecules encoding the same. The invention also relates to selective binding agents, vectors, host cells, and methods for producing FGFR-L polypeptides. The invention further relates to pharmaceutical compositions and methods for the diagnosis, treatment, amelioration, and/or prevention of diseases, disorders, and conditions associated with FGFR-L polypeptides.

BACKGROUND OF THE INVENTION

[0003] Technical advances in the identification, cloning, expression, and manipulation of nucleic acid molecules and the deciphering of the human genome have greatly accelerated the discovery of novel therapeutics. Rapid nucleic acid sequencing. techniques can now generate sequence information at unprecedented rates and, coupled with computational analyses, allow the assembly of overlapping sequences into partial and entire genomes and the identification of polypeptide-encoding regions. A comparison of a predicted amino acid sequence against a database compilation of known amino acid sequences allows one to determine the extent of homology to previously identified sequences and/or structural landmarks. The cloning and expression of a polypeptide-encoding region of a nucleic acid molecule provides a polypeptide product for structural and functional analyses. The manipulation of nucleic acid molecules and encoded polypeptides may confer advantageous properties on a product for use as a therapeutic.

[0004] In spite of the significant technical advances in genome research over the past decade, the potential for the development of novel therapeutics based on the human genome is still largely unrealized. Many genes encoding potentially beneficial polypeptide therapeutics or those encoding polypeptides, which may act as “targets” for therapeutic molecules, have still not been identified. Accordingly, it is an object of the invention to identify novel polypeptides, and nucleic acid molecules encoding the same, which have diagnostic or therapeutic benefit.

SUMMARY OF THE INVENTION

[0005] The present invention relates to novel FGFR-L nucleic acid molecules and encoded polypeptides.

[0006] The invention provides for an isolated nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of:

[0007] (a) the nucleotide sequence as set forth in either SEQ ID NO: 1 or SEQ ID NO: 4;

[0008] (b) the nucleotide sequence of the DNA insert in ATCC Deposit No. ______;

[0009] (c) a nucleotide sequence encoding the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

[0010] (d) a nucleotide sequence which hybridizes under moderately or highly stringent conditions to the complement of any of (a)-(c); and

[0011] (e) a nucleotide sequence complementary to any of (a)-(c).

[0012] The invention also provides for an isolated nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of:

[0013] (a) a nucleotide sequence encoding a polypeptide which is at least about 70 percent identical to the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

[0014] (b) a nucleotide sequence encoding an allelic variant or splice variant of the nucleotide sequence as set forth in either SEQ ID NO: 1 or SEQ ID NO: 4, the nucleotide sequence of the DNA insert in ATCC Deposit No. ______, or (a);

[0015] (c) a region of the nucleotide sequence of either SEQ ID NO: 1 or SEQ ID NO: 4, the DNA insert in ATCC Deposit No. ______, (a), or (b) encoding a polypeptide fragment of at least about 25 amino acid residues, wherein the polypeptide fragment has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, or is antigenic;

[0016] (d) a region of the nucleotide sequence of either SEQ ID NO: 1 or SEQ ID NO: 4, the DNA insert in ATCC Deposit No. ______, or any of (a)-(c) comprising a fragment of at least about 16 nucleotides;

[0017] (e) a nucleotide sequence which hybridizes under moderately or highly stringent conditions to the complement of any of (a)-(d); and

[0018] (f) a nucleotide sequence complementary to any of (a)-(d).

[0019] The invention further provides for an isolated nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of:

[0020] (a) a nucleotide sequence encoding a polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one conservative amino acid substitution, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

[0021] (b) a nucleotide sequence encoding a polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one amino acid insertion, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

[0022] (c) a nucleotide sequence encoding a polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one amino acid deletion, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

[0023] (d) a nucleotide sequence encoding a polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 which has a C- and/or N-terminal truncation, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

[0024] (e) a nucleotide sequence encoding a polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one modification selected from the group consisting of amino acid substitutions, amino acid insertions, amino acid deletions, C-terminal truncation, and N-terminal truncation, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

[0025] (f) a nucleotide sequence of any of (a)-(e) comprising a fragment of at least about 16 nucleotides;

[0026] (g) a nucleotide sequence which hybridizes under moderately or highly stringent conditions to the complement of any of (a)-(f); and

[0027] (h) a nucleotide sequence complementary to any of (a)-(e).

[0028] The present invention provides for an isolated polypeptide comprising an amino acid sequence selected from the group consisting of:

[0029] (a) the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5; and

[0030] (b) the amino acid sequence encoded by the DNA insert in ATCC Deposit No. ______.

[0031] The invention also provides for an isolated polypeptide comprising the amino acid sequence selected from the group consisting of

[0032] (a) the amino acid sequence as set forth in SEQ ID NO: 3 or SEQ ID NO: 6, optionally further comprising an amino-terminal methionine;

[0033] (b) an amino acid sequence for an ortholog of either SEQ ID NO: 2 or SEQ ID NO: 5;

[0034] (c) an amino acid sequence which is at least about 70 percent identical to the amino acid sequence of either SEQ ID NO: 2 or SEQ ID NO: 5, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

[0035] (d) a fragment of the amino acid sequence set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 comprising at least about 25 amino acid residues, wherein the fragment has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, or is antigenic; and

[0036] (e) an amino acid sequence for an allelic variant or splice variant of the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, the amino acid sequence encoded by the DNA insert in ATCC Deposit No. ______, or any of (a)-(c).

[0037] The invention further provides for an isolated polypeptide comprising the amino acid sequence selected from the group consisting of:

[0038] (a) the amino acid sequence as se t forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one conservative amino acid substitution, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

[0039] (1) the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one amino acid insertion, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

[0040] (c) the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one amino acid deletion, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

[0041] (d) the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 which has a C- and/or N-terminal truncation, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5; and

[0042] (e) the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one modification selected from the group consisting of amino acid substitutions, amino acid insertions, amino acid deletions, C-terminal truncation, and N-terminal truncation, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5.

[0043] Also provided are fusion polypeptides comprising FGFR-L amino acid sequences.

[0044] The present invention also provides for an expression vector comprising the isolated nucleic acid molecules as set forth herein, recombinant host cells comprising the recombinant nucleic acid molecules as set forth herein, and a method of producing an FGFR-L polypeptide comprising culturing the host cells and optionally isolating the polypeptide so produced.

[0045] A transgenic non-human animal comprising a nucleic acid molecule encoding an FGFR-L polypeptide is also encompassed by the invention. The FGFR-L nucleic acid molecules are introduced into the animal in a manner that allows expression and increased levels of an FGFR-L polypeptide, which may include increased circulating levels. Alternatively, the FGFR-L nucleic acid molecules are introduced into the animal in a manner that prevents expression of endogenous FGFR-L polypeptide (i.e., generates a transgenic animal possessing an FGFR-L polypeptide gene knockout). The transgenic non-human animal is preferably a mammal, and more preferably a rodent, such as a rat or a mouse.

[0046] Also provided are derivatives of the FGPR-L polypeptides of the present invention.

[0047] Additionally provided are selective binding agents such as antibodies and peptides capable of specifically binding the FGFR-L polypeptides of the invention. Such antibodies and peptides may be agonistic or antagonistic.

[0048] Pharmaceutical compositions comprising the nucleotides, polypeptides, or selective binding agents of the invention and one or more pharmaceutically acceptable formulation agents are also encompassed by the invention. The pharmaceutical compositions are used to provide therapeutically effective amounts of the nucleotides or polypeptides of the present invention. The invention is also directed to methods of using the polypeptides, nucleic acid molecules, and selective binding agents.

[0049] The FGFR-L polypeptides and nucleic acid molecules of the present invention may be used to treat, prevent, ameliorate, and/or detect diseases and disorders, including those recited herein.

[0050] The present invention also provides a method of assaying test molecules to identify a test molecule that binds to an FGFR-L polypeptide. The method comprises contacting an FGFR-L polypeptide with a test molecule to determine the extent of binding of the test molecule to the polypeptide. The method further comprises determining whether such test molecules are agonists or antagonists of an FGFR-L polypeptide. The present invention further provides a method of testing the impact of molecules on the expression of FGFR-L polypeptide or on the activity of FGFR-L polypeptide.

[0051] Methods of regulating expression and modulating (i.e., increasing or decreasing) levels of an FGFR-L polypeptide are also encompassed by the invention. One method comprises administering to an animal a nucleic acid molecule encoding an FGFR-L polypeptide. In another method, a nucleic acid molecule comprising elements that regulate or modulate the expression of an FGFR-L polypeptide may be administered. Examples of these methods include gene therapy, cell therapy, and anti-sense therapy as further described herein.

[0052] The FGFR-L polypeptide can be used for identifying ligands thereof. Various forms of “expression cloning” have been used for cloning ligands for receptors (e.g., Davis et al., 1996, Cell, 87:1161-69). These and other FGFR-L polypeptide ligand cloning experiments are described in greater detail herein. Isolation of an FGFR-L polypeptide ligand allows for the identification or development of novel agonists or antagonists of the FGFR-L polypeptide signaling pathway. Such agonists and antagonists include FGFR-L polypeptide ligands, anti-FGFR-L polypeptide ligand is antibodies and derivatives thereof, small molecules, or antisense oligonucleotides, any of which can be used for potentially treating one or more diseases or disorders, including those recited herein.

BRIEF DESCRIPTION OF THE FIGURES

[0053] FIGS. 1A-1C illustrate the nucleotide sequence of the murine FGFR-L gene (SEQ ID NO: 1) and the deduced amino acid sequence of murine FGFR-L polypeptide (SEQ ID NO: 2). The predicted signal peptide (underline) and transmembrane domain (double-underline) are indicated;

[0054] FIGS. 2A-2B illustrate the amino acid sequence alignment of murine FGFR-L polypeptide (Smaf2-00017-f4; SEQ ID NO: 2) and Iberian ribbed newt (Pleurodeles waltlii) Fibroblast Growth Factor Receptor-4 (PIR:B49151; SEQ ID NO: 7);

[0055] FIGS. 3A-3B illustrate the nucleotide sequence of a cDNA clone encoding the N-terminal portion of the human FGFR-L gene (SEQ ID NO: 4) and the deduced amino acid sequence of the N-terminal portion of the human FGFR-L polypeptide (SEQ ID NO: 5). The predicted signal peptide (underline) and transmembrane domain (double-underline) are indicated;

[0056]FIG. 4 illustrates the amino acid sequence alignment of murine FGFR-L polypeptide (SEQ ID NO: 2) and a virtual human FGFR-L polypeptide sequence (SEQ ID NO: 8) constructed from residues 1-472 of SEQ ID NO: 5 and residues 473-504 of GenBank Accession No. AJ277437. The predicted signal peptide (underline), transmembrane domain (double-underline), and N-linked glycosylation sites (bold) are indicated;

[0057]FIG. 5 illustrates the expression of FGFR-L MRNA as detected by Northern blot analysis in day 7, 11, 15, and 17 mouse embryos;

[0058]FIG. 6 illustrates the expression of FGFR-L mrRNA as detected by Northern blot analysis in murine heart, brain, spleen, lung, liver, skeletal muscle, kidney, and testis;

[0059]FIG. 7 illustrates the expression of FGFR-L mRNA as detected by Northern blot analysis in NIH 3T3 cells and F10, F4, and D3 mouse bone marrow-derived stromal cell lines;

[0060]FIG. 8 illustrates the expression of FGFR-L mRNA as detected by Northern blot analysis in human brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung, and peripheral blood leukocytes;

[0061]FIG. 9 illustrates the expression of FGFR-L mRNA as detected by Northern blot analysis in promyelocytic leukemia HL-60 cells, HeLa S3 cells, chronic myelogenous leukemia L-562 cells, lymphoblastic leukemia MOLT-4 cells, Burkitt's lymphoma Raji cells, colorectal adenocarcinoma SW480 cells, lung carcinoma A549 cells, and melanoma G361 cells;

[0062]FIG. 10 illustrates the expression of FGFR-L mRNA as detected by Northern blot analysis in human heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas;

[0063]FIG. 11 illustrates the expression of FGFR-L mRNA as detected by Northern blot analysis in 266-6 cells, AR42J cells, CaPan I cells, HIG-82 cells, OHS4 cells, SW 1353 cells, SW 872 cells, K562 (old, i.e., later passage) cells, K562 (new, i.e., earlier passage) cells, Jurkat cells, and F4 cells;

[0064] FIGS. 12A-12B illustrate the expression of FGFR-L mRNA as detected by Northern blot analysis in human adipose tissue (using a human FGFR-L-derived probe) and murine adipose tissue (using a murine FGFR-L-derived probe);

[0065]FIG. 13 illustrates the expression of FGFR-L mRNA in a number of murine tissues as detected in an RNAse protection assay. The absence of the cyclophilin band in the pancreas RNA sample suggests that thi sample was degraded;

[0066]FIG. 14 illustrates the expression of FGFR-L mRNA as detected by in situ hybridization in the peri-renal, white, and brown adipose tissue of a normal adult mouse (H&E=hematoxylin and eosin counterstaining; ISH=in situ hybridization);

[0067]FIG. 15 illustrates the. expression of FGFR-L mRNA as detected by in situ hybridization in the duodenum, ileum, colon, and pancreas of a normal adult mouse (H&E=hematoxylin and eosin counterstaining; ISH=in situ hybridization);

[0068]FIG. 16 illustrates the expression of FGFR-L mRNA as detected by in situ hybridization in the trachea, articular cartilage of the knee joint, spleen, and uterus of a normal adult mouse (H&E=hematoxylin and eosin counterstaining; ISH=in situ hybridization);

[0069]FIG. 17 illustrates the induction of FGFR-L MRNA in osteoblastic ST2 cells under conditions of osteoclastogenesis (i.e., 5-day exposure to vitamin D3 and dexamethasone);

[0070]FIG. 18 illustrates the results of Western blot analysis of E. coli-derived Des7-FGFR-L/ECD and CHO-derived FGFR-L/ECD-Fc proteins using FGFR-L polypeptide antiserum;

[0071]FIG. 19 illustrates the results of Western blot analysis of murine eye (lane 1) and adipose tissue (lane 2) using FGFR-L polypeptide antiserum;

[0072] FIGS. 20A-20B illustrate the results of FACS analysis on F4 and D3 bone marrow stromal cells using FGFR-L polypeptide antiserum;

[0073] FIGS. 21A-21D illustrate the results of proliferation assays using D3 bone marrow stromal cells (either untransduced or transduced with a construct encoding FGFR-L polypeptide) following 72 hour exposure to rhuPDGF (panel A), rhuFGF-2 (panel B), rhuFGF-4 (panel C), or rhuFGF-6 (panel D);

[0074]FIG. 22 illustrates the results of proliferation assays using A5-F bone marrow stromal cells following exposure to E. coli-derived Des7-FGFR-L/ECD protein and serum, PDGF, FGF-2, FGF-4, or FGF-6;

[0075]FIG. 23 illustrates the results of proliferation assays using A5-F bone marrow stromal cells following exposure to CHO-derived FGFR-L/ECD-Fc protein and serum, PDGF, FGF-4, or FGF-6;

[0076]FIG. 24 illustrates the expression of the neomycin resistance gene as detected by Northern blot analysis of peripheral blood mononuclear cell (PBMN) RNA from two FGFR-L/neo-transduced mice (lanes 1 and 2) and two neo-transduced control mice (lanes 3 and 4).

DETAILED DESCRIPTION OF THE INVENTION

[0077] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All references cited in this application are expressly incorporated by reference herein.

[0078] Definitions

[0079] The terms “FGFR-L gene” or “FGFR-L nucleic acid molecule” or “FGFR-L polynucleotide” refer to a nucleic acid molecule comprising or consisting of a nucleotide sequence as set forth in either SEQ ID NO: 1 or SEQ ID NO: 4, a nucleotide sequence encoding the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, a nucleotide sequence of the DNA insert in ATCC Deposit No. ______, and nucleic acid molecules as defined herein.

[0080] The term “FGFR-L polypeptide allelic variant” refers to one of several possible naturally occurring alternate forms of a gene occupying a given locus on a chromosome of an organism or a population of organisms.

[0081] The term “FGFR-L polypeptide splice variant” refers to a nucleic acid molecule, usually RNA, which is generated by alternative processing of intron sequences in an RNA transcript of FGFR-L polypeptide amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5.

[0082] The term “isolated nucleic acid molecule” refers to a nucleic acid molecule of the invention that (1) has been separated from at least about 50 percent of proteins, lipids, carbohydrates, or other materials with which it is naturally found when total nucleic acid is isolated from the source cells, (2) is not linked to all or a portion of a polynucleotide to which the “isolated nucleic acid molecule” is linked in nature, (3) is operably linked to a polynucleotide which it is not linked to in nature, or (4) does not occur in nature as part of a larger polynucleotide sequence. Preferably, the isolated nucleic acid molecule of the present invention is substantially free from any other contaminating nucleic acid molecule(s) or other contaminants that are found in its natural environment that would interfere with its use in polypeptide production or its therapeutic, diagnostic, prophylactic or research use.

[0083] The term “nucleic acid sequence” or “nucleic acid molecule” refers to a DNA or RNA sequence. The term encompasses molecules formed from any of the known base analogs of DNA and RNA such as, but not limited to 4-acetylcytosine, 8-hydroxy-N6-methyladenosine, aziridinyl-cytosine, pseudoisocytosine, 5-(carboxyhydroxylmethyl) uracil, 5-fluorouracil, 5-bromouracil, 5-carboxymethylaminomethyl-2-thiouracil, 5-carboxy-methylaminomethyluracil, dihydrouracil, inosine, N6-iso-pentenyladenine, 1-methyladenine, 1-methylpseudouracil, 1-methylguanine, 1-methylinosine, 2,2-dimethyl-guanine, 2-methyladenine, -2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-methyladenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyamino-methyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarbonyl-methyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid, oxybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, N-uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid, pseudouracil, queosine, 2-thiocytosine, and 2,6-diaminopurine.

[0084] The term “vector” is used to refer to any molecule (e.g., nucleic acid, plasmid, or virus) used to transfer coding information to a host cell.

[0085] The term “expression vector” refers to a vector that is suitable for transformation of a host cell and contains nucleic acid sequences that direct and/or control the expression of inserted heterologous nucleic acid sequences. Expression includes, but is not limited to, processes such as transcription, translation, and RNA splicing, if introns are present.

[0086] The term “operably linked” is used herein to refer to an arrangement of flanking sequences wherein the flanking sequences so described are configured or assembled so as to perform their usual function. Thus, a flanking sequence operably linked to a coding sequence may be capable of effecting the replication, transcription and/or translation of the coding sequence. For example, a coding sequence is operably linked to a promoter when the promoter is capable of directing transcription of that coding sequence. A flanking sequence need not be contiguous with the coding sequence, so long as it functions correctly. Thus, for example, intervening untranslated yet transcribed sequences can be present between a promoter sequence and the coding sequence and the promoter sequence can still be considered “operably linked” to the coding sequence.

[0087] The term “host cell” is used to refer to a cell which has been transformed, or is capable of being transformed with a nucleic acid sequence and then of expressing a selected gene of interest. The term includes the progeny of the parent cell, whether or not the progeny is identical in morphology or in genetic make-up to the original parent, so long as the selected gene is present.

[0088] The term “FGFR-L polypeptide” refers to a polypeptide comprising the amino acid sequence of either SEQ ID NO.: 2 or SEQ ID NO: 5 and related polypeptides. Related polypeptides include FGFR-L polypeptide fragments, FGFR-L polypeptide orthologs, FGFR-L polypeptide variants, and FGFR-L polypeptide derivatives, which possess at least one activity of the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. FGFR-L polypeptides may be mature polypeptides, as defined herein, and may or may not have an amino-terminal methionine residue, depending on the method by which they are prepared.

[0089] The term “FGFR-L polypeptide fragment” refers to a polypeptide that comprises a truncation at the amino-terminus (with or without a leader sequence) and/or a truncation at the carboxyl-terminus of the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. The term “FGFR-L polypeptide fragment” also refers to amino-terminal and/or carboxyl-terminal truncations of FGFR-L polypeptide orthologs, FGFR-L polypeptide derivatives, or FGFR-L polypeptide variants, or to amino-terminal and/or carboxyl-terminal truncations of the polypeptides encoded by FGFR-L polypeptide allelic variants or FGFR-L polypeptide splice variants. FGFR-L polypeptide fragments may result from alternative RNA splicing or from in vivo protease activity. Membrane-bound forms of an FGFR-L polypeptide are also contemplated by the present invention. In preferred embodiments, truncations and/or deletions comprise about 10 amino acids, or about 20 amino acids, or about 50 amino acids, or about 75 amino acids, or about 100 amino acids, or more than about 100 amino acids. The polypeptide fragments so produced will comprise about 25 contiguous amino acids, or about 50 amino acids, or about 75. amino acids, or about 100 amino acids, or about 150 amino acids, or about 200 amino acids, or more than about 200 amino acids. Such FGFR-L polypeptide fragments may optionally comprise an amino-terminal methionine residue. It will be appreciated that such fragments can be used, for example, to generate antibodies to FGFR-L polypeptides.

[0090] The term “FGFR-L polypeptide ortholog” refers to a polypeptide from another species that corresponds to FGFR-L polypeptide amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. For example, mouse and human FGFR-L polypeptides are considered orthologs of each other.

[0091] The term “FGFR-L polypeptide variants” refers to FGFR-L polypeptides comprising amino acid sequences having one or more amino acid sequence substitutions, deletions (such as internal deletions and/or FGFR-L polypeptide fragments), and/or additions (such as internal additions and/or FGFR-L fusion polypeptides) as compared to the FGFR-L polypeptide amino acid sequence set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 (with or without a leader sequence). Variants may be naturally occurring (e.g., FGFR-L polypeptide allelic variants, FGFR-L polypeptide orthologs, and FGFR-L polypeptide splice variants) or artificially constructed. Such FGFR-L polypeptide variants may be prepared from the corresponding nucleic acid molecules having a DNA sequence that varies accordingly from the DNA sequence as set forth in either SEQ ID NO: 1 or SEQ ID NO: 4. In preferred embodiments, the variants have from 1 to 3, or from 1 to 5, or from 1 to 10, or from 1 to 15, or from 1 to 20, or from 1 to 25, or from 1 to 50, or from 1 to 75, or from 1 to 100, or more than 100 amino acid substitutions, insertions, additions and/or deletions, wherein the substitutions may be conservative, or non-conservative, or any combination thereof.

[0092] The term “FGFR-L polypeptide derivatives” refers to the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, FGFR-L polypeptide fragments, FGFR-L polypeptide orthologs, or FGFR-L polypeptide variants, as defined herein, that have been chemically modified. The term “FGFR-L polypeptide derivatives” also refers to the polypeptides encoded by FGFR-L polypeptide allelic variants or FGFR-L polypeptide splice variants, as defined herein, that have been chemically modified.

[0093] The term “mature FGFR-L polypeptide” refers to an FGFR-L polypeptide lacking a leader sequence. A mature FGFR-L polypeptide may also include other modifications such as proteolytic processing of the amino-terminus (with or without a leader sequence) and/or the carboxyl-terminus, cleavage of a smaller polypeptide from a larger precursor, N-linked and/or O-linked glycosylation, and the like. An exemplary mature FGFR-L polypeptide is depicted by the amino acid sequence of either SEQ ID NO: 3 or SEQ ID NO: 6.

[0094] The term “FGFR-L fusion polypeptide” refers to a fusion of one or more amino acids (such as a heterologous protein or peptide) at the amino- or carboxyl-terminus of the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, FGFR-L polypeptide fragments, FGFR-L polypeptide orthologs, FGFR-L polypeptide variants, or FGFR-L derivatives, as defined herein. The term “FGFR-L fusion polypeptide” also refers to a fusion of one or more amino acids at the amino- or carboxyl-terminus of the polypeptide encoded by FGFR-L polypeptide allelic variants or FGFR-L polypeptide splice variants, as defined herein.

[0095] The term “biologically active FGFR-L polypeptides” refers to FGFR-L polypeptides having at least one activity characteristic of the polypeptide comprising the amino acid sequence of either SEQ ID NO: 2 or SEQ ID NO: 5. In addition, an FGFR-L polypeptide may be active as an immunogen; that is, the FGFR-L polypeptide contains at least one epitope to which antibodies may be raised.

[0096] The term “isolated polypeptide” refers to a polypeptide of the present invention that (1) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is naturally found when isolated from the source cell, (2) is not linked (by covalent or noncovalent interaction) to all or a portion of a polypeptide to which the “isolated polypeptide” is linked in nature, (3) is operably linked (by covalent or noncovalent interaction) to a polypeptide with which it is not linked in nature, or (4) does not occur in nature. Preferably, the isolated polypeptide is substantially free from any other contaminating polypeptides or other contaminants that are found in its natural environment that would interfere with its therapeutic, diagnostic, prophylactic or research use.

[0097] The term “identity,” as known in the art, refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by comparing the sequences. In the art, “identity” also means the degree of sequence relatedness between nucleic acid molecules or polypeptides, as the case may be, as determined by the match between strings of two or more nucleotide or two or more amino acid sequences. “Identity” measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e., “algorithms”).

[0098] The term “similarity” is a related concept, but in contrast to “identity,” “similarity” refers to a measure of relatedness which includes both identical matches and conservative substitution matches. If two polypeptide sequences have, for example, {fraction (10/20)} identical amino acids, and the remainder are all non-conservative substitutions, then the percent identity and similarity would both be 50%. If in the same example, there are five more positions where there are conservative substitutions, then the percent identity remains 50%, but the percent similarity would be 75% ({fraction (15/20)}). Therefore, in cases where there are conservative substitutions, the percent similarity between two polypeptides will be higher than the percent identity between those two polypeptides.

[0099] The term “naturally occurring” or “native” when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to materials which are found in nature and are not manipulated by man. Similarly, “non-naturally occurring” or “non-native” as used herein refers to a material that is not found in nature or that has been structurally modified or synthesized by man.

[0100] The terms “effective amount” and “therapeutically effective amount” each refer to the amount of an FGFR-L polypeptide or FGFR-L nucleic acid molecule used to support an observable level of one or more biological activities of the FGFR-L polypeptides as set forth herein.

[0101] The term “pharmaceutically acceptable carrier” or “physiologically acceptable carrier” as used herein refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of the FGFR-L polypeptide, FGFR-L nucleic acid molecule, or FGFR-L selective binding agent as a pharmaceutical composition.

[0102] The term “antigen” refers to a molecule or a portion of a molecule capable of being bound by a selective binding agent, such as an antibody, and additionally capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. An antigen may have one or more epitopes.

[0103] The term “selective binding agent” refers to a molecule or molecules having specificity for an FGFR-L polypeptide. As used herein, the terms, “specific” and “specificity” refer to the ability of the selective binding agents to bind to human FGFR-L polypeptides and not to bind to human non-FGFR-L polypeptides. It will be appreciated, however, that the selective binding agents may also bind orthologs of the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, that is, interspecies versions thereof, such as mouse and rat FGFR-L polypeptides.

[0104] The term “transduction” is used to refer to the transfer of genes from one bacterium to another, usually by a phage. “Transduction” also refers to the acquisition and transfer of eukaryotic cellular sequences by retroviruses.

[0105] The term “transfection” is used to refer to the uptake of foreign or exogenous DNA by a cell, and a cell has been “transfected” when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art and are disclosed herein. See, e.g., Graham et al., 1973, Virology 52:456; Sambrook et al., Molecular Cloning, A Laboratory Manual (Cold Spring Harbor Laboratories, 1989); Davis et al., Basic Methods in Molecular Biology (Elsevier, 1986); and Chu et al., 1981, Gene 13:197. Such techniques can be used to introduce one or more exogenous DNA moieties into suitable host cells.

[0106] The term “transformation” as used herein refers to a change in a cell's genetic characteristics, and a cell has been transformed when it has been modified to contain a new DNA. For example, a cell is transformed where it is genetically modified from its native state. Following transfection or transduction, the transforming DNA may recombine with that of the cell by physically integrating into a chromosome of the cell, may be maintained transiently as an episomal element without being replicated, or may replicate independently as a plasmid. A cell is considered to have been stably transformed when the DNA is replicated with the division of the cell.

[0107] Relatedness of Nucleic Acid Molecules and/or Polypeptides

[0108] It is understood that related nucleic acid molecules include allelic or splice variants of the nucleic acid molecule of either SEQ ID NO: 1 or SEQ ID NO: 4, and include sequences which are complementary to any of the above nucleotide sequences. Related nucleic acid molecules also include a nucleotide sequence encoding a polypeptide comprising or consisting essentially of a substitution, modification, addition and/or deletion of one or more amino acid residues compared to the polypeptide in either SEQ ID NO: 2 or SEQ ID NO: 5. Such related FGFR-L polypeptides may comprise, for example, an addition and/or a deletion of one or more N-linked or O-linked glycosylation sites or an addition and/or a deletion of one or more cysteine residues.

[0109] Related nucleic acid molecules also include fragments of FGFR-L nucleic acid molecules which encode a polypeptide of at least about 25 contiguous amino acids, or about 50 amino acids, or about 75 amino acids, or about 100 amino acids, or about 150 amino acids, or about 200 amino acids, or more than about 200 amino acid residues of the FGFR-L polypeptide of either SEQ ID NO: 2 or SEQ ID NO: 5.

[0110] In addition, related FGFR-L nucleic acid molecules also include those molecules which comprise nucleotide sequences which hybridize under moderately or highly stringent conditions as defined herein with the fully complementary sequence of the FGFR-L nucleic acid molecule of either SEQ ID NO: 1 or SEQ ID NO: 4, or of a molecule encoding a polypeptide, which polypeptide comprises the amino acid sequence as shown in either SEQ ID NO: 2 or SEQ ID NO: 5, or of a nucleic acid fragment as defined herein, or of a nucleic acid fragment encoding a polypeptide as defined herein. Hybridization probes may be prepared using the FGFR-L sequences provided herein to screen cDNA, genomic or synthetic DNA libraries for related sequences. Regions of the DNA and/or amino acid sequence of FGFR-L polypeptide that exhibit significant identity to known sequences are readily determined using sequence alignment algorithms as described herein and those regions may be used to design probes for screening.

[0111] The term “highly stringent conditions” refers to those conditions that are designed to permit hybridization of DNA strands whose sequences are highly complementary, and to exclude hybridization of significantly mismatched DNAs. Hybridization stringency is principally determined by temperature, ionic strength, and the concentration of denaturing agents such as formamide. Examples of “highly stringent conditions” for hybridization and washing are 0.015 M sodium FGFR-Loride, 0.0015 M sodium citrate at 65-68° C. or 0.015 M sodium FGFR-Loride, 0.0015 M sodium citrate, and 50% formamide at 42° C. See Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual (2nd ed., Cold Spring Harbor Laboratory, 1989); Anderson et al., Nucleic Acid Hybridisation: A Practical Approach Ch. 4 (IRL Press Limited).

[0112] More stringent conditions (such as higher temperature, lower ionic strength, higher formamide, or other denaturing agent) may also be used—however, the rate of hybridization will be affected. Other agents may be included in the hybridization and Washing buffers for the purpose of reducing non-specific and/or background hybridization. Examples are 0.1% bovine serum albumin, 0.1% polyvinyl-pyrrolidone, 0.1% sodium pyrophosphate, 0.1% sodium dodecylsulfate, NaDodSO₄, (SDS), ficoll, Denhardt's solution, sonicated salmon sperm DNA (or another non-complementary DNA), and dextran sulfate, although other suitable agents can also be used. The concentration and types of these additives can be changed without substantially affecting the stringency of the hybridization conditions. Hybridization experiments are usually carried out at pH 6.8-7.4; however, at typical ionic strength conditions, the rate of hybridization is nearly independent of pH. See Anderson et al., Nucleic Acid Hybridisation: A Practical Approach Ch. 4 (IRL Press Limited).

[0113] Factors affecting the stability of DNA duplex include base composition, length, and degree of base pair mismatch. Hybridization conditions can be adjusted by one skilled in the art in order to accommodate these variables and allow DNAs of different sequence relatedness to form hybrids. The melting temperature of a perfectly matched DNA duplex can be estimated by the following equation:

T _(m)(° C.)=81.5+16.6(log[Na+])+0.41(% G+C)−600/N−0.72(% formamide)

[0114] where N is the length of the duplex formed, [Na+] is the molar concentration of the sodium ion in the hybridization or washing solution, % G+C is the percentage of (guanine+cytosine) bases in the hybrid. For imperfectly matched hybrids, the melting temperature is reduced by approximately 1° C. for each 1% mismatch.

[0115] The term “moderately stringent conditions” refers to conditions under which a DNA duplex with a greater degree of base pair mismatching than could occur under “highly stringent conditions” is able to form. Examples of typical “moderately stringent conditions” are 0.015 M sodium FGFR-Loride, 0.0015 M sodium citrate at 50-65° C. or 0.015 M sodium FGFR-Loride, 0.0015 M sodium citrate, and 20% formamide at 37-50° C. By way of example, “moderately stringent conditions” of 50° C. in 0.015 M sodium ion will allow about a 21% mismatch.

[0116] It will be appreciated by those skilled in the art that there is no absolute distinction between “highly stringent conditions” and “moderately stringent conditions.” For example, at 0.015 M sodium ion (no formamide), the melting temperature of perfectly matched long DNA is about 71° C. With a wash at 65° C. (at the same ionic strength), this would allow for approximately a 6% mismatch. To capture more distantly related sequences, one skilled in the art can simply lower the temperature or raise the ionic strength.

[0117] A good estimate of the melting temperature in 1M NaCl* for oligonucleotide probes up to about 20nt is given by:

Tm=2° C. per A−T base pair+4° C. per G−C base pair

[0118] *The sodium ion concentration in 6× salt sodium citrate (SSC) is 1M. See Suggs et al., Developmental Biology Using Purified Genes 683 (Brown and Fox, eds., 1981).

[0119] High stringency washing conditions for oligonucleotides are usually at a temperature of 0-5° C. below the Tm of the oligonucleotide in 6× SSC, 0.1% SDS.

[0120] In another embodiment, related nucleic acid molecules comprise or consist of a nucleotide sequence that is at least about 70 percent identical to the nucleotide sequence as shown in either SEQ ID NO: 1 or SEQ ID NO: 4, or comprise or consist essentially of a nucleotide sequence encoding a polypeptide that is at least about 70 percent identical to the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. In preferred embodiments, the nucleotide sequences are about 75 percent, or about 80 percent, or about 85 percent, or about 90 percent, or about 95, 96, 97, 98, or 99 percent identical to the nucleotide sequence as shown in either SEQ ID NO: 1 or SEQ ID NO: 4, or the nucleotide sequences encode a polypeptide that is about 75 percent, or about 80 percent, or about 85 percent, or about 90 percent, or about 95, 96, 97, 98, or 99 percent identical to the polypeptide sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5.

[0121] Related nucleic acid molecules encode polypeptides possessing at least one activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5.

[0122] Differences in the nucleic acid sequence may result in conservative and/or non-conservative modifications of the amino acid sequence relative to the amino acid sequence of either SEQ ID NO: 2 or SEQ ID NO: 5.

[0123] Conservative modifications to the amino acid sequence of either SEQ ID NO: 2 or SEQ ID NO: 5 (and the corresponding modifications to the encoding nucleotides) will produce a polypeptide having functional and chemical characteristics similar to those of FGFR-L polypeptides. In contrast, substantial modifications in the functional and/or chemical characteristics of FGFR-L polypeptides may be accomplished by selecting substitutions in the amino acid sequence of either SEQ ID NO: 2 or SEQ ID NO: 5 that differ significantly in their effect on maintaining (a) the structure of the molecular backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.

[0124] For example, a “conservative amino acid substitution” may involve a substitution of a native amino acid residue with a normative residue such that there is little or no effect on the polarity or charge of the amino acid residue at that position. Furthermore, any native residue in the polypeptide may also be substituted with alanine, as has been previously described for “alanine scanning mutagenesis.”

[0125] Conservative amino acid substitutions also encompass non-naturally occurring amino acid residues that are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include peptidomimetics, and other reversed or inverted forms of amino acid moieties.

[0126] Naturally occurring residues may be divided into classes based on common side chain properties:

[0127] 1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile;

[0128] 2) neutral hydrophilic: Cys, Ser, Thr;

[0129] 3) acidic: Asp, Glu;

[0130] 4) basic: Asn, Gln, His, Lys, Arg;

[0131] 5) residues that influence chain orientation: Gly, Pro; and

[0132] 6) aromatic: Trp, Tyr, Phe.

[0133] For example, non-conservative substitutions may involve the exchange of a member of one of these classes for a member from another class. Such substituted residues may be introduced into regions of the human FGFR-L polypeptide that are homologous with non-human FGFR-L polypeptides, or into the non-homologous regions of the molecule.

[0134] In making such changes, the hydropathic index of amino acids may be considered.

[0135] Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics. The hydropathic indices are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (−0.4); threonine (−0.7); serine (−0.8); tryptophan (−0.9); tyrosine (−1.3); proline (−1.6); histidine (−3.2); glutamate (−3.5); glutamine (−3.5); aspartate (−3.5); asparagine (−3.5); lysine (−3.9); and arginine (−4.5).

[0136] The importance of the hydropathic amino acid index in conferring interactive biological function on a protein is generally understood in the art (Kyte et al., 1982, J. Mol. Biol. 157:105-31). It is known that certain amino acids maybe substituted for other amino acids having a similar hydropathic index or score and still retain a similar biological activity. In making changes based upon the hydropathic index, the substitution of amino acids whose hydropathic indices are within ±2 is preferred, those which are within ±1 are particularly preferred, and those within ±0.5 are even more particularly preferred.

[0137] It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity, particularly where the biologically functionally equivalent protein or peptide thereby created is intended for use in immunological embodiments, as in the present case. The greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with its immunogenicity and antigenicity, i.e., with a biological property of the protein.

[0138] The following hydrophilicity values have been assigned to these amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0±1); glutamate (+3.0±1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (−0.4); proline (−0.5±1); alanine (−0.5); histidine (−0.5); cysteine (−1.0); methionine (−1.3); valine (−1.5); leucine (−1.8); isoleucine (−1.8); tyrosine (−2.3); phenylalanine (−2.5); and tryptophan (−3.4). In making changes based upon similar hydrophilicity values, the substitution of amino acids whose hydrophilicity values are within ±2 is preferred, those which are within ±1 are particularly preferred, and those within ±0.5 are even more particularly preferred. One may also identify epitopes from primary amino acid sequences on the basis of hydrophilicity. These regions are also referred to as “epitopic core regions.”

[0139] Desired amino acid substitutions (whether conservative or non-conservative) can be determined by those skilled in the art at the time such substitutions are desired. For example, amino acid substitutions can be used to identify important residues of the FGFR-L polypeptide, or to increase or decrease the affinity of the FGFR-L polypeptides described herein. Exemplary amino acid substitutions are set forth in Table I. TABLE I Amino Acid Substitutions Original Residues Exemplary Substitutions Preferred Substitutions Ala Val, Leu, Ile Val Arg Lys, Gln, Asn Lys Asn Gln Gln Asp Glu Glu Cys Ser, Ala Ser Gln Asn Asn Glu Asp Asp Gly Pro, Ala Ala His Asn, Gln, Lys, Arg Arg Ile Leu, Val, Met, Ala, Leu Phe, Norleucine Leu Norleucine, Ile, Ile Val, Met, Ala, Phe Lys Arg, 1,4 Diamino-butyric Arg Acid, Gln, Asn Met Leu, Phe, Ile Leu Phe Leu, Val, Ile, Ala, Leu Tyr Pro Ala Gly Ser Thr, Ala, Cys Thr Thr Ser Ser Trp Tyr, Phe Tyr Tyr Trp, Phe, Thr, Ser Phe Val Ile, Met, Leu, Phe, Leu Ala, Norleucine

[0140] A skilled artisan will be able to determine suitable variants of the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 using well-known techniques. For identifying suitable areas of the molecule that may be changed without destroying biological activity, one skilled in the art may target areas not believed to be important for activity. For example, when similar polypeptides with similar activities from the same species or from other species are known, one skilled in the art may compare the amino acid sequence of an FGFR-L polypeptide to such similar polypeptides. With such a comparison, one can identify residues and portions of the molecules that are conserved among similar polypeptides. It will be appreciated that changes in areas of the FGFR-L molecule that are not conserved relative to such similar polypeptides would be less likely to adversely affect the biological activity and/or structure of an FGFR-L polypeptide. One skilled in the art would also know that, even in relatively conserved regions, one may substitute chemically similar amino acids for the naturally occurring residues while retaining activity (conservative amino acid residue substitutions). Therefore, even areas that may be important for biological activity or for structure may be subject to conservative amino acid substitutions without destroying the biological activity or without adversely affecting the polypeptide structure.

[0141] Additionally, one skilled in the art can review structure-function studies identifying residues in similar polypeptides that are important for activity or structure. In view of such a comparison, one can predict the importance of amino acid residues in an FGFR-L polypeptide that correspond to amino acid residues that are important for activity or structure in similar polypeptides. One skilled in the art may opt for chemically similar amino acid substitutions for such predicted important amino acid residues of FGFR-L polypeptides.

[0142] One skilled in the art can also analyze the three-dimensional structure and amino acid sequence in relation to that structure in similar polypeptides. In view of such information, one skilled in the art may predict the alignment of amino acid residues of FGFR-L polypeptide with respect to its three dimensional structure. One skilled in the art may choose not to make radical changes to amino acid residues predicted to be on the surface of the protein, since such residues may be involved in important interactions with other molecules. Moreover, one skilled in the art may generate test variants containing a single amino acid substitution at each amino acid residue. The variants could be screened using activity assays known to those with skill in the art. Such variants could be used to gather information about suitable variants. For example, if one discovered that a change to a particular amino acid residue resulted in destroyed, undesirably reduced, or unsuitable activity, variants with such a change would be avoided. In other words, based on information gathered from such routine experiments, one skilled in the art can readily determine the amino acids where further substitutions should be avoided either alone or in combination with other mutations.

[0143] A number of scientific publications have been devoted to the prediction of secondary structure. See Moult, 1996, Curr. Opin. Biotechnol. 7:422-27; Chou et al., 1974, Biochemistry 13:222-45; Chou et al., 1974, Biochemistry 113:211-22; Chou et al., 1978, Adv. Enzymol. Relat. Areas Mol. Biol. 47:45-48; Chou et al., 1978, Ann. Rev. Biochem. 47:251-276; and Chou et al., 1979, Biophys. J 26:367-84. Moreover, computer programs are currently available to assist with predicting secondary structure. One method of predicting secondary structure is based upon homology modeling. For example, two polypeptides or proteins which have a sequence identity of greater than 30%, or similarity greater than 40%, often have similar structural topologies. The recent growth of the protein structural database (PDB) has provided enhanced predictability of secondary structure, including the potential number of folds within the structure of a polypeptide or protein. See Holm et al., 1999, Nucleic Acids Res. 27:244-47. It has been suggested that there are a limited number of folds in a given polypeptide or protein and that once a critical number of structures have been resolved, structural prediction will become dramatically more accurate (Brenner et al., 1997, Curr. Opin. Struct. Biol. 7:369-76).

[0144] Additional methods of predicting secondary structure include “threading” (Jones, 1997, Curr. Opin. Struct. Biol. 7:377-87; Sippl et al., 1996, Structure 4:15-19), “profile analysis” (Bowie et al., 1991, Science, 253:164-70; Gribskov et al., 1990, Methods Enzymol. 183:146-59; Gribskov et al., 1987, Proc. Nat. Acad. Sci. U.S.A. 84:4355-58), and “evolutionary linkage” (See Holm et aL, supra, and Brenner et al., supra).

[0145] Preferred FGFR-L polypeptide variants include glycosylation variants wherein the number and/or type of glycosylation sites have been altered compared to the amino acid sequence set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. In one embodiment, FGFR-L polypeptide variants comprise a greater or a lesser number of N-linked glycosylation sites than the amino acid sequence set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X may be any amino acid residue except proline. The substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions that eliminate this sequence will remove an existing N-linked carbohydrate chain. Also provided is a rearrangement of N-linked carbohydrate chains wherein one or more N-linked glycosylation sites (typically those that are naturally occurring) are eliminated and one or more new N-linked sites are created. Additional preferred FGFR-L variants include cysteine variants, wherein one or more cysteine residues are deleted or substituted with another amino acid (e.g., serine) as compared to the amino acid sequence set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. Cysteine variants are useful when FGFR-L polypeptides must be refolded into a biologically active conformation such as after the isolation of insoluble inclusion bodies. Cysteine variants generally have fewer cysteine residues than the native protein, and typically have an even number to minimize interactions resulting from unpaired cysteines.

[0146] In other embodiments, related nucleic acid molecules comprise or consist of a nucleotide sequence encoding a polypeptide as set forth in either Seq Id No: 2 or SEQ ID NO: 5 with at least one amino acid insertion and wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, or a

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 22 <210> SEQ ID NO 1 <211> LENGTH: 2277 <212> TYPE: DNA <213> ORGANISM: Mus musculus <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (87)..(1673) <221> NAME/KEY: sig_peptide <222> LOCATION: (87)..(146) <221> NAME/KEY: misc_feature <222> LOCATION: (1208)..(1271) <223> OTHER INFORMATION: predicted transmembrane domain <400> SEQUENCE: 1 gacctgggtc ttgcgggcct gagccctgag tggcgtccag tccagctccc agtgaccgcg 60 cccctgcttc aggtccgacc ggcgag atg acg cgg agc ccc gcg ctg ctg ctg 113 Met Thr Arg Ser Pro Ala Leu Leu Leu 1 5 ctg cta ttg ggg gcc ctc ccg tcg gct gag gcg gcg cga gga ccc cca 161 Leu Leu Leu Gly Ala Leu Pro Ser Ala Glu Ala Ala Arg Gly Pro Pro 10 15 20 25 aga atg gca gac aaa gtg gtc cca cgg cag gtg gcc cgc ctg ggc cgc 209 Arg Met Ala Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg 30 35 40 act gtg cgg cta cag tgc cca gtg gag ggg gac cca cca ccg ttg acc 257 Thr Val Arg Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr 45 50 55 atg tgg acc aaa gat ggc cgc aca atc cac agt ggc tgg agc cgc ttc 305 Met Trp Thr Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe 60 65 70 cgt gtg ctg ccc cag ggt ctg aag gtg aag gag gtg gag gcc gag gat 353 Arg Val Leu Pro Gln Gly Leu Lys Val Lys Glu Val Glu Ala Glu Asp 75 80 85 gcc ggt gtt tat gtg tgc aag gcc acc aat ggc ttt ggc agc ctc agc 401 Ala Gly Val Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser 90 95 100 105 gtc aac tac act ctc atc atc atg gat gat att agt cca ggg aag gag 449 Val Asn Tyr Thr Leu Ile Ile Met Asp Asp Ile Ser Pro Gly Lys Glu 110 115 120 agc cct ggg cca ggt ggt tct tcg ggg ggc cag gag gac cca gcc agc 497 Ser Pro Gly Pro Gly Gly Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser 125 130 135 cag cag tgg gca cgg cct cgc ttc aca cag ccc tcc aag atg agg cgc 545 Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg 140 145 150 cga gtg att gca cgg cct gtg ggt agc tct gtg cgg ctc aag tgt gtg 593 Arg Val Ile Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val 155 160 165 gcc agt ggg cac cca cgg cca gac atc atg tgg atg aag gat gac cag 641 Ala Ser Gly His Pro Arg Pro Asp Ile Met Trp Met Lys Asp Asp Gln 170 175 180 185 acc ttg acg cat cta gag gct agt gaa cac aga aag aag aag tgg aca 689 Thr Leu Thr His Leu Glu Ala Ser Glu His Arg Lys Lys Lys Trp Thr 190 195 200 ctg agc ttg aag aac ctg aag cct gaa gac agt ggc aag tac acg tgc 737 Leu Ser Leu Lys Asn Leu Lys Pro Glu Asp Ser Gly Lys Tyr Thr Cys 205 210 215 cgt gta tct aac aag gcc ggt gcc atc aac gcc acc tac aaa gtg gat 785 Arg Val Ser Asn Lys Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp 220 225 230 gta atc cag cgg act cgt tcc aag cct gtg ctc aca ggg aca cac cct 833 Val Ile Gln Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro 235 240 245 gtg aac aca acg gtg gac ttc ggt ggg aca acg tcc ttc cag tgc aag 881 Val Asn Thr Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys 250 255 260 265 gtg cgc agt gac gtg aag cct gtg atc cag tgg ctg aag cgg gtg gag 929 Val Arg Ser Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu 270 275 280 tac ggc tcc gag gga cgc cac aac tcc acc att gat gtg ggt ggc cag 977 Tyr Gly Ser Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln 285 290 295 aag ttt gtg gtg ttg ccc acg ggt gat gtg tgg tca cgg cct gat ggc 1025 Lys Phe Val Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly 300 305 310 tcc tac ctc aac aag ctg ctc atc tct cgg gcc cgc cag gat gat gct 1073 Ser Tyr Leu Asn Lys Leu Leu Ile Ser Arg Ala Arg Gln Asp Asp Ala 315 320 325 ggc atg tac atc tgc cta ggt gca aat acc atg ggc tac agt ttc cgt 1121 Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg 330 335 340 345 agc gcc ttc ctc act gta tta cca gac ccc aaa cct cca ggg cct cct 1169 Ser Ala Phe Leu Thr Val Leu Pro Asp Pro Lys Pro Pro Gly Pro Pro 350 355 360 atg gct tct tca tcg tca tcc aca agc ctg cca tgg cct gtg gtg atc 1217 Met Ala Ser Ser Ser Ser Ser Thr Ser Leu Pro Trp Pro Val Val Ile 365 370 375 ggc atc cca gct ggt gct gtc ttc atc cta ggc act gtg ctg ctc tgg 1265 Gly Ile Pro Ala Gly Ala Val Phe Ile Leu Gly Thr Val Leu Leu Trp 380 385 390 ctt tgc cag acc aag aag aag cca tgt gcc cca gca tct aca ctt cct 1313 Leu Cys Gln Thr Lys Lys Lys Pro Cys Ala Pro Ala Ser Thr Leu Pro 395 400 405 gtg cct ggg cat cgt ccc cca ggg aca tcc cga gaa cgc agt ggt gac 1361 Val Pro Gly His Arg Pro Pro Gly Thr Ser Arg Glu Arg Ser Gly Asp 410 415 420 425 aag gac ctg ccc tca ttg gct gtg ggc ata tgt gag gag cat gga tcc 1409 Lys Asp Leu Pro Ser Leu Ala Val Gly Ile Cys Glu Glu His Gly Ser 430 435 440 gcc atg gcc ccc cag cac atc ctg gcc tct ggc tca act gct ggc ccc 1457 Ala Met Ala Pro Gln His Ile Leu Ala Ser Gly Ser Thr Ala Gly Pro 445 450 455 aag ctg tac ccc aag cta tac aca gat gtg cac aca cac aca cat aca 1505 Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Val His Thr His Thr His Thr 460 465 470 cac acc tgc act cac acg ctc tca tgt gga ggg caa ggt tca tca aca 1553 His Thr Cys Thr His Thr Leu Ser Cys Gly Gly Gln Gly Ser Ser Thr 475 480 485 cca gca tgt cca cta tca gtg cta aat aca gcg aat ctc caa gca ctg 1601 Pro Ala Cys Pro Leu Ser Val Leu Asn Thr Ala Asn Leu Gln Ala Leu 490 495 500 505 tgt cct gag gta ggc ata tgg ggg cca agg caa cag gtt ggg aga att 1649 Cys Pro Glu Val Gly Ile Trp Gly Pro Arg Gln Gln Val Gly Arg Ile 510 515 520 gag aac aat gga gga aga gta tct tagggtgcct tatggtggac actcacaaac 1703 Glu Asn Asn Gly Gly Arg Val Ser 525 ttggccatat agatgtatgt actaccagat gaacagccag ccagattcac acacgcacat 1763 gtttaaacgt gtaaacgtgt gcacaactgc acacacaacc tgagaaacct tcaggaggat 1823 ttgtggtgtg actttgcagt gacatgtagc gatggctagt tgaaggaatc tccctcatgt 1883 cttagtggtc atggccactt ccccacccct gcccatctgt gttcctgcct ggccttggtg 1943 tgcttccgtg tgccctgggt atcaggagcc tatcatcaac ctgactgggg tgagcagtgc 2003 agccatgcct ggaggtttga gccaccctcc ccttgctaga gagaagggcc tcaatattta 2063 tatttaagaa atgaaataat attaataata atgtaaggag ggctgggaca cagggactct 2123 ggccttccct ggggcctggg acctgcctgg ccttgtggtt acattgggta ccctcactgt 2183 ccatggctgc ctggtctctg taattttata tagagtttga gctgaagcct cgtatattta 2243 atttattttg ttaaacaaga aaaaaaaaaa aaaa 2277 <210> SEQ ID NO 2 <211> LENGTH: 529 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 2 Met Thr Arg Ser Pro Ala Leu Leu Leu Leu Leu Leu Gly Ala Leu Pro 1 5 10 15 Ser Ala Glu Ala Ala Arg Gly Pro Pro Arg Met Ala Asp Lys Val Val 20 25 30 Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro 35 40 45 Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg 50 55 60 Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu 65 70 75 80 Lys Val Lys Glu Val Glu Ala Glu Asp Ala Gly Val Tyr Val Cys Lys 85 90 95 Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Ile Ile 100 105 110 Met Asp Asp Ile Ser Pro Gly Lys Glu Ser Pro Gly Pro Gly Gly Ser 115 120 125 Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg 130 135 140 Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val 145 150 155 160 Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro 165 170 175 Asp Ile Met Trp Met Lys Asp Asp Gln Thr Leu Thr His Leu Glu Ala 180 185 190 Ser Glu His Arg Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Lys 195 200 205 Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser Asn Lys Ala Gly 210 215 220 Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser 225 230 235 240 Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe 245 250 255 Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro 260 265 270 Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ser Glu Gly Arg His 275 280 285 Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr 290 295 300 Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu 305 310 315 320 Ile Ser Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly 325 330 335 Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu 340 345 350 Pro Asp Pro Lys Pro Pro Gly Pro Pro Met Ala Ser Ser Ser Ser Ser 355 360 365 Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val 370 375 380 Phe Ile Leu Gly Thr Val Leu Leu Trp Leu Cys Gln Thr Lys Lys Lys 385 390 395 400 Pro Cys Ala Pro Ala Ser Thr Leu Pro Val Pro Gly His Arg Pro Pro 405 410 415 Gly Thr Ser Arg Glu Arg Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala 420 425 430 Val Gly Ile Cys Glu Glu His Gly Ser Ala Met Ala Pro Gln His Ile 435 440 445 Leu Ala Ser Gly Ser Thr Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr 450 455 460 Thr Asp Val His Thr His Thr His Thr His Thr Cys Thr His Thr Leu 465 470 475 480 Ser Cys Gly Gly Gln Gly Ser Ser Thr Pro Ala Cys Pro Leu Ser Val 485 490 495 Leu Asn Thr Ala Asn Leu Gln Ala Leu Cys Pro Glu Val Gly Ile Trp 500 505 510 Gly Pro Arg Gln Gln Val Gly Arg Ile Glu Asn Asn Gly Gly Arg Val 515 520 525 Ser <210> SEQ ID NO 3 <211> LENGTH: 509 <212> TYPE: PRT <213> ORGANISM: Mus musculus <220> FEATURE: <221> NAME/KEY: TRANSMEM <222> LOCATION: (355)..(375) <400> SEQUENCE: 3 Ala Arg Gly Pro Pro Arg Met Ala Asp Lys Val Val Pro Arg Gln Val 1 5 10 15 Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro Val Glu Gly Asp 20 25 30 Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg Thr Ile His Ser 35 40 45 Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu Lys Val Lys Glu 50 55 60 Val Glu Ala Glu Asp Ala Gly Val Tyr Val Cys Lys Ala Thr Asn Gly 65 70 75 80 Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Ile Ile Met Asp Asp Ile 85 90 95 Ser Pro Gly Lys Glu Ser Pro Gly Pro Gly Gly Ser Ser Gly Gly Gln 100 105 110 Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro 115 120 125 Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val Gly Ser Ser Val 130 135 140 Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro Asp Ile Met Trp 145 150 155 160 Met Lys Asp Asp Gln Thr Leu Thr His Leu Glu Ala Ser Glu His Arg 165 170 175 Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Lys Pro Glu Asp Ser 180 185 190 Gly Lys Tyr Thr Cys Arg Val Ser Asn Lys Ala Gly Ala Ile Asn Ala 195 200 205 Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser Lys Pro Val Leu 210 215 220 Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe Gly Gly Thr Thr 225 230 235 240 Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro Val Ile Gln Trp 245 250 255 Leu Lys Arg Val Glu Tyr Gly Ser Glu Gly Arg His Asn Ser Thr Ile 260 265 270 Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr Gly Asp Val Trp 275 280 285 Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu Ile Ser Arg Ala 290 295 300 Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr Met 305 310 315 320 Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu Pro Asp Pro Lys 325 330 335 Pro Pro Gly Pro Pro Met Ala Ser Ser Ser Ser Ser Thr Ser Leu Pro 340 345 350 Trp Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile Leu Gly 355 360 365 Thr Val Leu Leu Trp Leu Cys Gln Thr Lys Lys Lys Pro Cys Ala Pro 370 375 380 Ala Ser Thr Leu Pro Val Pro Gly His Arg Pro Pro Gly Thr Ser Arg 385 390 395 400 Glu Arg Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala Val Gly Ile Cys 405 410 415 Glu Glu His Gly Ser Ala Met Ala Pro Gln His Ile Leu Ala Ser Gly 420 425 430 Ser Thr Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Val His 435 440 445 Thr His Thr His Thr His Thr Cys Thr His Thr Leu Ser Cys Gly Gly 450 455 460 Gln Gly Ser Ser Thr Pro Ala Cys Pro Leu Ser Val Leu Asn Thr Ala 465 470 475 480 Asn Leu Gln Ala Leu Cys Pro Glu Val Gly Ile Trp Gly Pro Arg Gln 485 490 495 Gln Val Gly Arg Ile Glu Asn Asn Gly Gly Arg Val Ser 500 505 <210> SEQ ID NO 4 <211> LENGTH: 1450 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (33)..(1448) <221> NAME/KEY: sig_peptide <222> LOCATION: (33)..(104) <221> NAME/KEY: misc_feature <222> LOCATION: (1167)..(1229) <400> SEQUENCE: 4 gcggccgcga ccccaggtcc ggacaggccg ag atg acg ccg agc ccc ctg ttg 53 Met Thr Pro Ser Pro Leu Leu 1 5 ctg ctc ctg ctg ccg ccg ctg ctg ctg ggg gcc ttc cca ccg gcc gcc 101 Leu Leu Leu Leu Pro Pro Leu Leu Leu Gly Ala Phe Pro Pro Ala Ala 10 15 20 gcc gcc cga ggc ccc cca aag atg gcg gac aag gtg gtc cca cgg cag 149 Ala Ala Arg Gly Pro Pro Lys Met Ala Asp Lys Val Val Pro Arg Gln 25 30 35 gtg gcc cgg ctg ggc cgc act gtg cgg ctg cag tgc cca gtg gag ggg 197 Val Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro Val Glu Gly 40 45 50 55 gac ccg ccg ccg ctg acc atg tgg acc aag gat ggc cgc acc atc cac 245 Asp Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg Thr Ile His 60 65 70 agc ggc tgg agc cgc ttc cgc gtg ctg ccg cag ggg ctg aag gtg aag 293 Ser Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu Lys Val Lys 75 80 85 cag gtg gag cgg gag gat gcc ggc gtg tac gtg tgc aag gcc acc aac 341 Gln Val Glu Arg Glu Asp Ala Gly Val Tyr Val Cys Lys Ala Thr Asn 90 95 100 ggc ttc ggc agc ctg agc gtc aac tac acc ctc gtc gtg ctg gat gac 389 Gly Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Val Val Leu Asp Asp 105 110 115 att agc cca ggg aag gag agc ctg ggg ccc gac agc tcc tct ggg ggt 437 Ile Ser Pro Gly Lys Glu Ser Leu Gly Pro Asp Ser Ser Ser Gly Gly 120 125 130 135 caa gag gac ccc gcc agc cag cag tgg gca cga ccg cgc ttc aca cag 485 Gln Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln 140 145 150 ccc tcc aag atg agg cgc cgg gtg atc gca cgg ccc gtg ggt agc tcc 533 Pro Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val Gly Ser Ser 155 160 165 gtg cgg ctc aag tgc gtg gcc agc ggg cac cct cgg ccc gac atc acg 581 Val Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro Asp Ile Thr 170 175 180 tgg atg aag gac gac cag gcc ttg acg cgc cca gag gcc gct gag ccc 629 Trp Met Lys Asp Asp Gln Ala Leu Thr Arg Pro Glu Ala Ala Glu Pro 185 190 195 agg aag aag aag tgg aca ctg agc ctg aag aac ctg cgg ccg gag gac 677 Arg Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Arg Pro Glu Asp 200 205 210 215 agc ggc aaa tac acc tgc cgc gtg tcg aac cgc gcg ggc gcc atc aac 725 Ser Gly Lys Tyr Thr Cys Arg Val Ser Asn Arg Ala Gly Ala Ile Asn 220 225 230 gcc acc tac aag gtg gat gtg atc cag cgg acc cgt tcc aag ccc gtg 773 Ala Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser Lys Pro Val 235 240 245 ctc aca ggc acg cac ccc gtg aac acg acg gtg gac ttc ggg ggg acc 821 Leu Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe Gly Gly Thr 250 255 260 acg tcc ttc cag tgc aag gtg cgc agc gac gtg aag ccg gtg atc cag 869 Thr Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro Val Ile Gln 265 270 275 tgg ctg aag cgc gtg gag tac ggc gct gag ggc cgc cac aac tcc acc 917 Trp Leu Lys Arg Val Glu Tyr Gly Ala Glu Gly Arg His Asn Ser Thr 280 285 290 295 atc gat gtg ggc ggc cag aag ttt gtg gtg ctg ccc acg ggt gac gtg 965 Ile Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr Gly Asp Val 300 305 310 tgg tcg cgg ccc gac ggc tcc tac ctc aat aag ctg ctc atc acc cgt 1013 Trp Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu Ile Thr Arg 315 320 325 gcc cgc cag gac gat gcg ggc atg tac atc tgc ctt ggc gcc aac acc 1061 Ala Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr 330 335 340 atg ggc tac agc ttc cgc agc gcc ttc ctc acc gtg ctg cca gac cca 1109 Met Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu Pro Asp Pro 345 350 355 aaa ccg cca ggg cca cct gtg gcc tcc tcg tcc tcg gcc act agc ctg 1157 Lys Pro Pro Gly Pro Pro Val Ala Ser Ser Ser Ser Ala Thr Ser Leu 360 365 370 375 ccg tgg ccc gtg gtc atc ggc atc cca gcc ggc gct gtc ttc atc ctg 1205 Pro Trp Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile Leu 380 385 390 ggc acc ctg ctc ctg tgg ctt tgc cag gcc cag aag aag ccg tgc acc 1253 Gly Thr Leu Leu Leu Trp Leu Cys Gln Ala Gln Lys Lys Pro Cys Thr 395 400 405 ccc gcg cct gcc cct ccc ctg cct ggg cac cgc ccg ccg ggg acg gcc 1301 Pro Ala Pro Ala Pro Pro Leu Pro Gly His Arg Pro Pro Gly Thr Ala 410 415 420 cgc gac cgc agc gga gac aag gac ctt ccc tcg ttg gcc gcc ctc agc 1349 Arg Asp Arg Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala Ala Leu Ser 425 430 435 gct ggc cct ggt gtg ggg ctg tgt gag gag cat ggg tct ccg gca gcc 1397 Ala Gly Pro Gly Val Gly Leu Cys Glu Glu His Gly Ser Pro Ala Ala 440 445 450 455 ccc cag cac tta ctg ggc cca ggc cca gtt gct ggc cct aag ttg tac 1445 Pro Gln His Leu Leu Gly Pro Gly Pro Val Ala Gly Pro Lys Leu Tyr 460 465 470 ccc ta 1450 Pro <210> SEQ ID NO 5 <211> LENGTH: 472 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 5 Met Thr Pro Ser Pro Leu Leu Leu Leu Leu Leu Pro Pro Leu Leu Leu 1 5 10 15 Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg Gly Pro Pro Lys Met Ala 20 25 30 Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg 35 40 45 Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr 50 55 60 Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu 65 70 75 80 Pro Gln Gly Leu Lys Val Lys Gln Val Glu Arg Glu Asp Ala Gly Val 85 90 95 Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr 100 105 110 Thr Leu Val Val Leu Asp Asp Ile Ser Pro Gly Lys Glu Ser Leu Gly 115 120 125 Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp 130 135 140 Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile 145 150 155 160 Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly 165 170 175 His Pro Arg Pro Asp Ile Thr Trp Met Lys Asp Asp Gln Ala Leu Thr 180 185 190 Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys Lys Trp Thr Leu Ser Leu 195 200 205 Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser 210 215 220 Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln 225 230 235 240 Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr 245 250 255 Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser 260 265 270 Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ala 275 280 285 Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val 290 295 300 Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu 305 310 315 320 Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr 325 330 335 Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe 340 345 350 Leu Thr Val Leu Pro Asp Pro Lys Pro Pro Gly Pro Pro Val Ala Ser 355 360 365 Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro 370 375 380 Ala Gly Ala Val Phe Ile Leu Gly Thr Leu Leu Leu Trp Leu Cys Gln 385 390 395 400 Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro Ala Pro Pro Leu Pro Gly 405 410 415 His Arg Pro Pro Gly Thr Ala Arg Asp Arg Ser Gly Asp Lys Asp Leu 420 425 430 Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro Gly Val Gly Leu Cys Glu 435 440 445 Glu His Gly Ser Pro Ala Ala Pro Gln His Leu Leu Gly Pro Gly Pro 450 455 460 Val Ala Gly Pro Lys Leu Tyr Pro 465 470 <210> SEQ ID NO 6 <211> LENGTH: 448 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: TRANSMEM <222> LOCATION: (355)..(375) <400> SEQUENCE: 6 Ala Arg Gly Pro Pro Lys Met Ala Asp Lys Val Val Pro Arg Gln Val 1 5 10 15 Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro Val Glu Gly Asp 20 25 30 Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg Thr Ile His Ser 35 40 45 Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu Lys Val Lys Gln 50 55 60 Val Glu Arg Glu Asp Ala Gly Val Tyr Val Cys Lys Ala Thr Asn Gly 65 70 75 80 Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Val Val Leu Asp Asp Ile 85 90 95 Ser Pro Gly Lys Glu Ser Leu Gly Pro Asp Ser Ser Ser Gly Gly Gln 100 105 110 Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro 115 120 125 Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val Gly Ser Ser Val 130 135 140 Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro Asp Ile Thr Trp 145 150 155 160 Met Lys Asp Asp Gln Ala Leu Thr Arg Pro Glu Ala Ala Glu Pro Arg 165 170 175 Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Arg Pro Glu Asp Ser 180 185 190 Gly Lys Tyr Thr Cys Arg Val Ser Asn Arg Ala Gly Ala Ile Asn Ala 195 200 205 Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser Lys Pro Val Leu 210 215 220 Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe Gly Gly Thr Thr 225 230 235 240 Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro Val Ile Gln Trp 245 250 255 Leu Lys Arg Val Glu Tyr Gly Ala Glu Gly Arg His Asn Ser Thr Ile 260 265 270 Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr Gly Asp Val Trp 275 280 285 Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu Ile Thr Arg Ala 290 295 300 Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr Met 305 310 315 320 Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu Pro Asp Pro Lys 325 330 335 Pro Pro Gly Pro Pro Val Ala Ser Ser Ser Ser Ala Thr Ser Leu Pro 340 345 350 Trp Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile Leu Gly 355 360 365 Thr Leu Leu Leu Trp Leu Cys Gln Ala Gln Lys Lys Pro Cys Thr Pro 370 375 380 Ala Pro Ala Pro Pro Leu Pro Gly His Arg Pro Pro Gly Thr Ala Arg 385 390 395 400 Asp Arg Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala Ala Leu Ser Ala 405 410 415 Gly Pro Gly Val Gly Leu Cys Glu Glu His Gly Ser Pro Ala Ala Pro 420 425 430 Gln His Leu Leu Gly Pro Gly Pro Val Ala Gly Pro Lys Leu Tyr Pro 435 440 445 <210> SEQ ID NO 7 <211> LENGTH: 574 <212> TYPE: PRT <213> ORGANISM: Pleurodeles waltlii <400> SEQUENCE: 7 Met Gly Val Gln Lys Asp Ser Arg Asp Ile Arg Trp Asn Arg Thr Thr 1 5 10 15 Arg Pro Leu Ala Leu Leu Leu Cys Gly Leu Leu Ala Phe Ser Ala Leu 20 25 30 Ser Cys Ala Arg Thr Leu Pro Glu Gly Arg Lys Ala Asn Leu Ala Glu 35 40 45 Leu Val Ser Glu Glu Glu Glu His Phe Leu Leu Asp Pro Gly Asn Ala 50 55 60 Leu Arg Leu Phe Cys Asp Thr Asn Gln Thr Thr Ile Val Asn Trp Tyr 65 70 75 80 Thr Glu Ser Thr Arg Leu Gln His Gly Gly Arg Ile Arg Leu Thr Asp 85 90 95 Thr Val Leu Glu Ile Ala Asp Val Thr Tyr Glu Asp Ser Gly Leu Tyr 100 105 110 Leu Cys Val Val Pro Gly Thr Gly His Ile Leu Arg Asn Phe Thr Ile 115 120 125 Ser Val Val Asp Ser Leu Ala Ser Gly Asp Asp Asp Asp Glu Asp His 130 135 140 Gly Arg Glu Asp Ser Ala Gly Asp Met Gly Glu Asp Pro Pro Tyr Ser 145 150 155 160 Thr Ser Tyr Arg Ala Pro Phe Trp Ser Gln Pro Gln Arg Met Asp Lys 165 170 175 Lys Leu Tyr Ala Val Pro Ala Gly Asn Thr Val Lys Phe Arg Cys Pro 180 185 190 Ser Ala Gly Asn Pro Thr Pro Gly Ile Arg Trp Leu Lys Asn Gly Arg 195 200 205 Glu Phe Gly Gly Glu His Arg Ile Gly Gly Ile Arg Leu Arg His Gln 210 215 220 His Trp Ser Leu Val Met Glu Ser Val Val Pro Ser Asp Arg Gly Asn 225 230 235 240 Tyr Thr Cys Leu Val Glu Asn Lys Phe Gly Ser Ile Ser Tyr Ser Tyr 245 250 255 Leu Leu Asp Val Leu Glu Arg Ser Pro His Arg Pro Ile Leu Gln Ala 260 265 270 Gly Leu Pro Ala Asn Thr Thr Ala Met Leu Gly Ser Asp Val Gln Phe 275 280 285 Phe Cys Lys Val Tyr Ser Asp Ala Gln Pro His Ile Gln Trp Leu Lys 290 295 300 His Ile Glu Val Asn Gly Ser Arg Tyr Gly Pro Asp Gly Val Pro Phe 305 310 315 320 Val Gln Val Leu Lys Thr Ala Asp Ile Asn Ser Ser Glu Val Glu Val 325 330 335 Leu Tyr Leu His Asn Val Ser Phe Glu Asp Ala Gly Glu Tyr Thr Cys 340 345 350 Leu Ala Gly Asn Ser Ile Gly Leu Ser Tyr Gln Ser Ala Trp Leu Thr 355 360 365 Val Leu Pro Glu Glu Asp Phe Ala Lys Glu Ala Glu Gly Pro Glu Thr 370 375 380 Arg Tyr Thr Asp Ile Ile Ile Tyr Thr Ser Gly Ser Leu Ala Leu Leu 385 390 395 400 Met Ala Ala Val Ile Val Val Leu Cys Arg Met Gln Leu Pro Pro Thr 405 410 415 Lys Thr His Leu Glu Pro Ala Thr Val His Lys Leu Ser Arg Phe Pro 420 425 430 Leu Met Arg Gln Phe Ser Leu Glu Ser Ser Ser Ser Gly Lys Ser Ser 435 440 445 Thr Ser Leu Val Arg Val Thr Arg Leu Ser Ser Ser Cys Thr Pro Met 450 455 460 Leu Pro Gly Val Leu Glu Phe Asp Leu Pro Leu Asp Ser Lys Trp Glu 465 470 475 480 Phe Pro Arg Glu Arg Leu Val Leu Gly Lys Pro Leu Gly Glu Gly Cys 485 490 495 Phe Gly Gln Val Val Arg Ala Glu Ala Tyr Gly Ile Asn Lys Asp Gln 500 505 510 Pro Asp Lys Ala Ile Thr Val Ala Ile Lys Ile Val Lys Asp Lys Gly 515 520 525 Thr Asp Lys Glu Leu Ser Asp Leu Ile Ser Glu Met Glu Leu Met Lys 530 535 540 Leu Met Gly Lys His Lys Asn Ile Ile Asn Leu Leu Gly Val Cys Thr 545 550 555 560 Gln Asp Gly Pro Leu Tyr Met Ile Val Glu Tyr Ala Ser Lys 565 570 <210> SEQ ID NO 8 <211> LENGTH: 504 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: virtual human FGFR-L amino acid sequence comprising residues 1-472 of SEQ ID NO: 5 and residues 473-504 of GenBank accession no. AJ277437 <400> SEQUENCE: 8 Met Thr Pro Ser Pro Leu Leu Leu Leu Leu Leu Pro Pro Leu Leu Leu 1 5 10 15 Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg Gly Pro Pro Lys Met Ala 20 25 30 Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg 35 40 45 Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr 50 55 60 Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu 65 70 75 80 Pro Gln Gly Leu Lys Val Lys Gln Val Glu Arg Glu Asp Ala Gly Val 85 90 95 Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr 100 105 110 Thr Leu Val Val Leu Asp Asp Ile Ser Pro Gly Lys Glu Ser Leu Gly 115 120 125 Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp 130 135 140 Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile 145 150 155 160 Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly 165 170 175 His Pro Arg Pro Asp Ile Thr Trp Met Lys Asp Asp Gln Ala Leu Thr 180 185 190 Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys Lys Trp Thr Leu Ser Leu 195 200 205 Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser 210 215 220 Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln 225 230 235 240 Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr 245 250 255 Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser 260 265 270 Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ala 275 280 285 Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val 290 295 300 Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu 305 310 315 320 Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr 325 330 335 Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe 340 345 350 Leu Thr Val Leu Pro Asp Pro Lys Pro Pro Gly Pro Pro Val Ala Ser 355 360 365 Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro 370 375 380 Ala Gly Ala Val Phe Ile Leu Gly Thr Leu Leu Leu Trp Leu Cys Gln 385 390 395 400 Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro Ala Pro Pro Leu Pro Gly 405 410 415 His Arg Pro Pro Gly Thr Ala Arg Asp Arg Ser Gly Asp Lys Asp Leu 420 425 430 Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro Gly Val Gly Leu Cys Glu 435 440 445 Glu His Gly Ser Pro Ala Ala Pro Gln His Leu Leu Gly Pro Gly Pro 450 455 460 Val Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Ile His Thr 465 470 475 480 His Thr His Thr His Ser His Thr His Ser His Val Glu Gly Lys Val 485 490 495 His Gln His Ile His Tyr Gln Cys 500 <210> SEQ ID NO 9 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Human immunodeficiency virus type 1 <400> SEQUENCE: 9 Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg 1 5 10 <210> SEQ ID NO 10 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: internalizing domain derived from HIV tat protein <400> SEQUENCE: 10 Gly Gly Gly Gly Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg 1 5 10 15 <210> SEQ ID NO 11 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: predicted signal peptide of murine FGFR-L polypeptide <400> SEQUENCE: 11 Met Thr Arg Ser Pro Ala Leu Leu Leu Leu Leu Leu Gly Ala Leu Pro 1 5 10 15 Ser Ala Glu Ala 20 <210> SEQ ID NO 12 <211> LENGTH: 25 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: predicted transmmebrane domain for murine FRL polypeptide <400> SEQUENCE: 12 Leu Pro Trp Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile 1 5 10 15 Leu Gly Thr Val Leu Leu Trp Leu Cys 20 25 <210> SEQ ID NO 13 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: oligonucleotide; PCR primer <400> SEQUENCE: 13 cgctgaccat gtggaccaag gatg 24 <210> SEQ ID NO 14 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: oligonucleotide; PCR primer <400> SEQUENCE: 14 cttgacccca gaaggagctg tcgg 24 <210> SEQ ID NO 15 <211> LENGTH: 504 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 Met Thr Pro Ser Pro Leu Leu Leu Leu Leu Leu Pro Pro Leu Leu Leu 1 5 10 15 Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg Gly Pro Pro Lys Met Ala 20 25 30 Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg 35 40 45 Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr 50 55 60 Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu 65 70 75 80 Pro Gln Gly Leu Lys Val Lys Gln Val Glu Arg Glu Asp Ala Gly Val 85 90 95 Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr 100 105 110 Thr Leu Val Val Leu Asp Asp Ile Ser Pro Gly Lys Glu Ser Leu Gly 115 120 125 Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp 130 135 140 Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile 145 150 155 160 Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly 165 170 175 His Pro Arg Pro Asp Ile Thr Trp Met Lys Asp Asp Gln Ala Leu Thr 180 185 190 Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys Lys Trp Thr Leu Ser Leu 195 200 205 Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser 210 215 220 Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln 225 230 235 240 Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr 245 250 255 Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser 260 265 270 Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ala 275 280 285 Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val 290 295 300 Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu 305 310 315 320 Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr 325 330 335 Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe 340 345 350 Leu Thr Val Leu Pro Asp Pro Lys Pro Pro Gly Pro Pro Val Ala Ser 355 360 365 Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro 370 375 380 Ala Gly Ala Val Phe Ile Leu Gly Thr Leu Leu Leu Trp Leu Cys Gln 385 390 395 400 Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro Ala Pro Pro Leu Pro Gly 405 410 415 His Arg Pro Pro Gly Thr Ala Arg Asp Arg Ser Gly Asp Lys Asp Leu 420 425 430 Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro Gly Val Gly Leu Cys Glu 435 440 445 Glu His Gly Ser Pro Ala Ala Pro Gln His Leu Leu Gly Pro Gly Pro 450 455 460 Val Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Ile His Thr 465 470 475 480 His Thr His Thr His Ser His Thr His Ser His Val Glu Gly Lys Val 485 490 495 His Gln His Ile His Tyr Gln Cys 500 <210> SEQ ID NO 16 <211> LENGTH: 3112 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (25)..(1536) <400> SEQUENCE: 16 gaccccaggt ccggacaggc cgag atg acg ccg agc ccc ctg ttg ctg ctc 51 Met Thr Pro Ser Pro Leu Leu Leu Leu 1 5 ctg ctg ccg ccg ctg ctg ctg ggg gcc ttc cca ccg gcc gcc gcc gcc 99 Leu Leu Pro Pro Leu Leu Leu Gly Ala Phe Pro Pro Ala Ala Ala Ala 10 15 20 25 cga ggc ccc cca aag atg gcg gac aag gtg gtc cca cgg cag gtg gcc 147 Arg Gly Pro Pro Lys Met Ala Asp Lys Val Val Pro Arg Gln Val Ala 30 35 40 cgg ctg ggc cgc act gtg cgg ctg cag tgc cca gtg gag ggg gac ccg 195 Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro Val Glu Gly Asp Pro 45 50 55 ccg ccg ctg acc atg tgg acc aag gat ggc cgc acc atc cac agc ggc 243 Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg Thr Ile His Ser Gly 60 65 70 tgg agc cgc ttc cgc gtg ctg ccg cag ggg ctg aag gtg aag cag gtg 291 Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu Lys Val Lys Gln Val 75 80 85 gag cgg gag gat gcc ggc gtg tac gtg tgc aag gcc acc aac ggc ttc 339 Glu Arg Glu Asp Ala Gly Val Tyr Val Cys Lys Ala Thr Asn Gly Phe 90 95 100 105 ggc agc ctt agc gtc aac tac acc ctc gtc gtg ctg gat gac att agc 387 Gly Ser Leu Ser Val Asn Tyr Thr Leu Val Val Leu Asp Asp Ile Ser 110 115 120 cca ggg aag gag agc ctg ggg ccc gac agc tcc tct ggg ggt caa gag 435 Pro Gly Lys Glu Ser Leu Gly Pro Asp Ser Ser Ser Gly Gly Gln Glu 125 130 135 gac ccc gcc agc cag cag tgg gca cga ccg cgc ttc aca cag ccc tcc 483 Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro Ser 140 145 150 aag atg agg cgc cgg gtg atc gca cgg ccc gtg ggt agc tcc gtg cgg 531 Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val Gly Ser Ser Val Arg 155 160 165 ctc aag tgc gtg gcc agc ggg cac cct cgg ccc gac atc acg tgg atg 579 Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro Asp Ile Thr Trp Met 170 175 180 185 aag gac gac cag gcc ttg acg cgc cca gag gcc gct gag ccc agg aag 627 Lys Asp Asp Gln Ala Leu Thr Arg Pro Glu Ala Ala Glu Pro Arg Lys 190 195 200 aag aag tgg aca ctg agc ctg aag aac ctg cgg ccg gag gac agc ggc 675 Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Arg Pro Glu Asp Ser Gly 205 210 215 aaa tac acc tgc cgc gtg tcg aac cgc gcg ggc gcc atc aac gcc acc 723 Lys Tyr Thr Cys Arg Val Ser Asn Arg Ala Gly Ala Ile Asn Ala Thr 220 225 230 tac aag gtg gat gtg atc cag cgg acc cgt tcc aag ccc gtg ctc aca 771 Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser Lys Pro Val Leu Thr 235 240 245 ggc acg cac ccc gtg aac acg acg gtg gac ttc ggg ggg acc acg tcc 819 Gly Thr His Pro Val Asn Thr Thr Val Asp Phe Gly Gly Thr Thr Ser 250 255 260 265 ttc cag tgc aag gtg cgc agc gac gtg aag ccg gtg atc cag tgg ctg 867 Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro Val Ile Gln Trp Leu 270 275 280 aag cgc gtg gag tac ggc gcc gag ggc cgc cac aac tcc acc atc gat 915 Lys Arg Val Glu Tyr Gly Ala Glu Gly Arg His Asn Ser Thr Ile Asp 285 290 295 gtg ggc ggc cag aag ttt gtg gtg ctg ccc acg ggt gac gtg tgg tcg 963 Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr Gly Asp Val Trp Ser 300 305 310 cgg ccc gac ggc tcc tac ctc aat aag ctg ctc atc acc cgt gcc cgc 1011 Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu Ile Thr Arg Ala Arg 315 320 325 cag gac gat gcg ggc atg tac atc tgc ctt ggc gcc aac acc atg ggc 1059 Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr Met Gly 330 335 340 345 tac agc ttc cgc agc gcc ttc ctc acc gtg ctg cca gac cca aaa ccg 1107 Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu Pro Asp Pro Lys Pro 350 355 360 caa ggg cca cct gtg gcc tcc tcg tcc tcg gcc act agc ctg ccg tgg 1155 Gln Gly Pro Pro Val Ala Ser Ser Ser Ser Ala Thr Ser Leu Pro Trp 365 370 375 ccc gtg gtc atc ggc atc cca gcc ggc gct gtc ttc atc ctg ggc acc 1203 Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile Leu Gly Thr 380 385 390 ctg ctc ctg tgg ctt tgc cag gcc cag aag aag ccg tgc acc ccc gcg 1251 Leu Leu Leu Trp Leu Cys Gln Ala Gln Lys Lys Pro Cys Thr Pro Ala 395 400 405 cct gcc cct ccc ctg cct ggg cac cgc ccg ccg ggg acg gcc ctc gac 1299 Pro Ala Pro Pro Leu Pro Gly His Arg Pro Pro Gly Thr Ala Leu Asp 410 415 420 425 cgc agc gga gac aag gac ctt ccc tcg ttg gcc gcc ctc agc gct ggc 1347 Arg Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala Ala Leu Ser Ala Gly 430 435 440 cct ggt gtg ggg ctg tgt gag gag cat ggg tct ccg gca gcc ccc cag 1395 Pro Gly Val Gly Leu Cys Glu Glu His Gly Ser Pro Ala Ala Pro Gln 445 450 455 cac tta ctg ggc cca ggc cca gtt gct ggc cct aag ttg tac ccc aaa 1443 His Leu Leu Gly Pro Gly Pro Val Ala Gly Pro Lys Leu Tyr Pro Lys 460 465 470 ctc tac aca gac atc cac aca cac aca cac aca cac tct cac aca cac 1491 Leu Tyr Thr Asp Ile His Thr His Thr His Thr His Ser His Thr His 475 480 485 tca cac gtg gag ggc aag gtc cac cag cac atc cac tat cag tgc 1536 Ser His Val Glu Gly Lys Val His Gln His Ile His Tyr Gln Cys 490 495 500 tagacggcac cgtatctgca gtgggcacgg gggggccggc cagacaggca gactgggagg 1596 atggaggacg gagctgcaga cgaaggcagg ggacccatgg cgaggaggaa tggccagcac 1656 cccaggcagt ctgtgtgtga ggcatagccc ctggacacac acacacagac acacacacta 1716 cctggatgca tgtatgcaca cacatgcgcg cacacgtgct ccctgaaggc acacgtacgc 1776 acacacgcac atgcacagat atgccgcctg ggcacacaga taagctgccc aaatgcacgc 1836 acacgcacag agacatgcca gaacatacaa ggacatgctg cctgaacata cacacgcaca 1896 cccatgcgca gatgtgctgc ctggacacac acacacacac ggatatgctg tctggacgca 1956 cacacgtgca gatatggtat ccggacacac acgtgcacag atatgctgcc tggacacaca 2016 gataatgctg ccttgacaca cacatgcacg gatattgcct ggacacacac acacacacgc 2076 gtgcacagat atgctgtctg gacaggcaca cacatgcaga tatgctgcct ggacacacac 2136 ttccagacac acgtgcacag gcgcagatat gctgcctgga cacacgcaga tatgctgtct 2196 agtcacacac acacgcagac atgctgtccg gacacacaca cgcatgcaca gatatgctgt 2256 ccggacacac acacgcacgc agatatgctg cctggacaca cacacagata atgctgcctc 2316 aacactcaca cacgtgcaga tattgcctgg acacacacat gtgcacagat atgctgtctg 2376 gacatgcaca cacgtgcaga tatgctgtcc ggatacacac gcacgcacac atgcagatat 2436 gctgcctggg cacacacttc cggacacaca tgcacacaca ggtgcagata tgctgcctgg 2496 acacacgcag actgacgtgc ttttgggagg gtgtgccgtg aagcctgcag tacgtgtgcc 2556 gtgaggctca tagttgatga gggactttcc ctgctccacc gtcactcccc caactctgcc 2616 cgcctctgtc cccgcctcag tccccgcctc catccccgcc tctgtcccct ggccttggcg 2676 gctatttttg ccacctgcct tgggtgccca ggagtcccct actgctgtgg gctggggttg 2736 ggggcacagc agccccaagc ctgagaggct ggagcccatg gctagtggct catccccact 2796 gcattctccc cctgacacag agaaggggcc ttggtattta tatttaagaa atgaagataa 2856 tattaataat gatggaagga agactgggtt gcagggactg tggtctctcc tggggcccgg 2916 gacccgcctg gtctttcagc catgctgatg accacacccc gtccaggcca gacaccaccc 2976 cccaccccac tgtcgtggtg gccccagatc tctgtaattt tatgtagagt ttgagctgaa 3036 gccccgtata tttaatttat tttgttaaac atgaaagtgc atcctttccc tccaaaaaaa 3096 aaaaaaaaaa aaaaaa 3112 <210> SEQ ID NO 17 <211> LENGTH: 504 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 Met Thr Pro Ser Pro Leu Leu Leu Leu Leu Leu Pro Pro Leu Leu Leu 1 5 10 15 Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg Gly Pro Pro Lys Met Ala 20 25 30 Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg 35 40 45 Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr 50 55 60 Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu 65 70 75 80 Pro Gln Gly Leu Lys Val Lys Gln Val Glu Arg Glu Asp Ala Gly Val 85 90 95 Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr 100 105 110 Thr Leu Val Val Leu Asp Asp Ile Ser Pro Gly Lys Glu Ser Leu Gly 115 120 125 Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp 130 135 140 Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile 145 150 155 160 Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly 165 170 175 His Pro Arg Pro Asp Ile Thr Trp Met Lys Asp Asp Gln Ala Leu Thr 180 185 190 Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys Lys Trp Thr Leu Ser Leu 195 200 205 Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser 210 215 220 Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln 225 230 235 240 Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr 245 250 255 Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser 260 265 270 Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ala 275 280 285 Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val 290 295 300 Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu 305 310 315 320 Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr 325 330 335 Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe 340 345 350 Leu Thr Val Leu Pro Asp Pro Lys Pro Gln Gly Pro Pro Val Ala Ser 355 360 365 Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro 370 375 380 Ala Gly Ala Val Phe Ile Leu Gly Thr Leu Leu Leu Trp Leu Cys Gln 385 390 395 400 Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro Ala Pro Pro Leu Pro Gly 405 410 415 His Arg Pro Pro Gly Thr Ala Leu Asp Arg Ser Gly Asp Lys Asp Leu 420 425 430 Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro Gly Val Gly Leu Cys Glu 435 440 445 Glu His Gly Ser Pro Ala Ala Pro Gln His Leu Leu Gly Pro Gly Pro 450 455 460 Val Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Ile His Thr 465 470 475 480 His Thr His Thr His Ser His Thr His Ser His Val Glu Gly Lys Val 485 490 495 His Gln His Ile His Tyr Gln Cys 500 <210> SEQ ID NO 18 <211> LENGTH: 3080 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (23)..(1534) <400> SEQUENCE: 18 ccccaggtcc ggacaggccg ag atg acg ccg agc ccc ctg ttg ctg ctc ctg 52 Met Thr Pro Ser Pro Leu Leu Leu Leu Leu 1 5 10 ctg ccg ccg ctg ctg ctg ggg gcc ttc cca ccg gcc gcc gcc gcc cga 100 Leu Pro Pro Leu Leu Leu Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg 15 20 25 ggc ccc cca aag atg gcg gac aag gtg gtc cca cgg cag gtg gcc cgg 148 Gly Pro Pro Lys Met Ala Asp Lys Val Val Pro Arg Gln Val Ala Arg 30 35 40 ctg ggc cgc act gtg cgg ctg cag tgc cca gtg gag ggg gac ccg ccg 196 Leu Gly Arg Thr Val Arg Leu Gln Cys Pro Val Glu Gly Asp Pro Pro 45 50 55 ccg ctg acc atg tgg acc aag gat ggc cgc acc atc cac agc ggc tgg 244 Pro Leu Thr Met Trp Thr Lys Asp Gly Arg Thr Ile His Ser Gly Trp 60 65 70 agc cgc ttc cgc gtg ctg ccg cag ggg ctg aag gtg aag cag gtg gag 292 Ser Arg Phe Arg Val Leu Pro Gln Gly Leu Lys Val Lys Gln Val Glu 75 80 85 90 cgg gag gat gcc ggc gtg tac gtg tgc aag gcc acc aac ggc ttc ggc 340 Arg Glu Asp Ala Gly Val Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly 95 100 105 agc ctt agc gtc aac tac acc ctc gtc gtg ctg gat gac att agc cca 388 Ser Leu Ser Val Asn Tyr Thr Leu Val Val Leu Asp Asp Ile Ser Pro 110 115 120 ggg aag gag agc ctg ggg ccc gac agc tcc tct ggg ggt caa gag gac 436 Gly Lys Glu Ser Leu Gly Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp 125 130 135 ccc gcc agc cag cag tgg gca cga ccg cgc ttc aca cag ccc tcc aag 484 Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys 140 145 150 atg agg cgc cgg gtg atc gca cgg ccc gtg ggt agc tcc gtg cgg ctc 532 Met Arg Arg Arg Val Ile Ala Arg Pro Val Gly Ser Ser Val Arg Leu 155 160 165 170 aag tgc gtg gcc agc ggg cac cct cgg ccc gac atc acg tgg atg aag 580 Lys Cys Val Ala Ser Gly His Pro Arg Pro Asp Ile Thr Trp Met Lys 175 180 185 gac gac cag gcc ttg acg cgc cca gag gcc gct gag ccc agg aag aag 628 Asp Asp Gln Ala Leu Thr Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys 190 195 200 aag tgg aca ctg agc ctg aag aac ctg cgg ccg gag gac agc ggc aaa 676 Lys Trp Thr Leu Ser Leu Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys 205 210 215 tac acc tgc cgc gtg tcg aac cgc gcg ggc gcc atc aac gcc acc tac 724 Tyr Thr Cys Arg Val Ser Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr 220 225 230 aag gtg gat gtg atc cag cgg acc cgt tcc aag ccc gtg ctc aca ggc 772 Lys Val Asp Val Ile Gln Arg Thr Arg Ser Lys Pro Val Leu Thr Gly 235 240 245 250 acg cac ccc gtg aac acg acg gtg gac ttc ggg ggg acc acg tcc ttc 820 Thr His Pro Val Asn Thr Thr Val Asp Phe Gly Gly Thr Thr Ser Phe 255 260 265 cag tgc aag gtg cgc agc gac gtg aag ccg gtg atc cag tgg ctg aag 868 Gln Cys Lys Val Arg Ser Asp Val Lys Pro Val Ile Gln Trp Leu Lys 270 275 280 cgc gtg gag tac ggc gcc gag ggc cgc cac aac tcc acc atc gat gtg 916 Arg Val Glu Tyr Gly Ala Glu Gly Arg His Asn Ser Thr Ile Asp Val 285 290 295 ggc ggc cag aag ttt gtg gtg ctg ccc acg ggt gac gtg tgg tcg cgg 964 Gly Gly Gln Lys Phe Val Val Leu Pro Thr Gly Asp Val Trp Ser Arg 300 305 310 ccc gac ggc tcc tac ctc aat aag ctg ctc atc acc cgt gcc cgc cag 1012 Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln 315 320 325 330 gac gat gcg ggc atg tac atc tgc ctt ggc gcc aac acc atg ggc tac 1060 Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr 335 340 345 agc ttc cgc agc gcc ttc ctc acc gtg ctg cca gac cca aaa ccg caa 1108 Ser Phe Arg Ser Ala Phe Leu Thr Val Leu Pro Asp Pro Lys Pro Gln 350 355 360 ggg cca cct gtg gcc tcc tcg tcc tcg gcc act agc ctg ccg tgg ccc 1156 Gly Pro Pro Val Ala Ser Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro 365 370 375 gtg gtc atc ggc atc cca gcc ggc gct gtc ttc atc ctg ggc acc ctg 1204 Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile Leu Gly Thr Leu 380 385 390 ctc ctg tgg ctt tgc cag gcc cag aag aag ccg tgc acc ccc gcg cct 1252 Leu Leu Trp Leu Cys Gln Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro 395 400 405 410 gcc cct ccc ctg cct ggg cac cgc ccg ccg ggg acg gcc cgc gac cgc 1300 Ala Pro Pro Leu Pro Gly His Arg Pro Pro Gly Thr Ala Arg Asp Arg 415 420 425 agc gga gac aag gac ctt ccc tcg ttg gcc gcc ctc agc gct ggc cct 1348 Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro 430 435 440 ggt gtg ggg ctg tgt gag gag cat ggg tct ccg gca gcc ccc cag cac 1396 Gly Val Gly Leu Cys Glu Glu His Gly Ser Pro Ala Ala Pro Gln His 445 450 455 tta ctg ggc cca ggc cca gtt gct ggc cct aag ttg tac ccc aaa ctc 1444 Leu Leu Gly Pro Gly Pro Val Ala Gly Pro Lys Leu Tyr Pro Lys Leu 460 465 470 tac aca gac atc cac aca cac aca cac aca cac tct cac aca cac tca 1492 Tyr Thr Asp Ile His Thr His Thr His Thr His Ser His Thr His Ser 475 480 485 490 cac gtg gag ggc aag gtc cac cag cac atc cac tat cag tgc 1534 His Val Glu Gly Lys Val His Gln His Ile His Tyr Gln Cys 495 500 tagacggcac cgtatctgca gtgggcacgg gggggccggc cagacaggca gactgggagg 1594 atggaggacg gagctgcaga cgaaggcagg ggacccatgg cgaggaggaa tggccagcac 1654 cccaggcagt ctgtgtgtga ggcatagccc ctggacacac acacacagac acacacacta 1714 cctggatgca tgtatgcaca cacatgcgcg cacacgtgct ccctgaaggc acacgtacgc 1774 acacacgcac atgcacagat atgccgcctg ggcacacaga taagctgccc aaatgcacgc 1834 acacgcacag agacatgcca gaacatacaa ggacatgctg cctgaacata cacacgcaca 1894 cccatgcgca gatgtgctgc ctggacacac acacacacac ggatatgctg tctggacgca 1954 cacacgtgca gatatggtat ccggacacac acgtgcacag atatgctgcc tggacacaca 2014 gataatgctg ccttgacaca cacatgcacg gatattgcct ggacacacac acacacacgc 2074 gtgcacagat atgctgtctg gacaggcaca cacatgcaga tatgctgcct ggacacacac 2134 ttccagacac acgtgcacag gcgcagatat gctgcctgga cacacgcaga tatgctgtct 2194 agtcacacac acacgcagac atgctgtccg gacacacaca cgcatgcaca gatatgctgt 2254 ccggacacac acacgcacgc agatatgctg cctggacaca cacacagata atgctgcctc 2314 aacactcaca cacgtgcaga tattgcctgg acacacacat gtgcacagat atgctgtctg 2374 gacatgcaca cacgtgcaga tatgctgtcc ggatacacac gcacgcacac atgcagatat 2434 gctgcctggg cacacacttc cggacacaca tgcacacaca ggtgcagata tgctgcctgg 2494 acacacgcag actgacgtgc ttttgggagg gtgtgccgtg aagcctgcag tacgtgtgcc 2554 gtgaggctca tagttgatga gggactttcc ctgctccacc gtcactcccc caactctgcc 2614 cgcctctgtc cccgcctcag tccccgcctc catccccgcc tctgtcccct ggccttggcg 2674 gctatttttg ccacctgcct tgggtgccca ggagtcccct actgctgtgg gctggggttg 2734 ggggcacagc agccccaagc ctgagaggct ggagcccatg gctagtggct catccccact 2794 gcattctccc cctgacacag agaaggggcc ttggtattta tatttaagaa atgaagataa 2854 tattaataat gatggaagga agactgggtt gcagggactg tggtctctcc tggggcccgg 2914 gacccgcctg gtctttcagc catgctgatg accacacccc gtccaggcca gacaccaccc 2974 cccaccccac tgtcgtggtg gccccagatc tctgtaattt tatgtagagt ttgagctgaa 3034 gccccgtata tttaatttat tttgttaaac atgaaagtgc atcctt 3080 <210> SEQ ID NO 19 <211> LENGTH: 504 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 19 Met Thr Pro Ser Pro Leu Leu Leu Leu Leu Leu Pro Pro Leu Leu Leu 1 5 10 15 Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg Gly Pro Pro Lys Met Ala 20 25 30 Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg 35 40 45 Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr 50 55 60 Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu 65 70 75 80 Pro Gln Gly Leu Lys Val Lys Gln Val Glu Arg Glu Asp Ala Gly Val 85 90 95 Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr 100 105 110 Thr Leu Val Val Leu Asp Asp Ile Ser Pro Gly Lys Glu Ser Leu Gly 115 120 125 Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp 130 135 140 Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile 145 150 155 160 Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly 165 170 175 His Pro Arg Pro Asp Ile Thr Trp Met Lys Asp Asp Gln Ala Leu Thr 180 185 190 Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys Lys Trp Thr Leu Ser Leu 195 200 205 Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser 210 215 220 Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln 225 230 235 240 Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr 245 250 255 Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser 260 265 270 Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ala 275 280 285 Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val 290 295 300 Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu 305 310 315 320 Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr 325 330 335 Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe 340 345 350 Leu Thr Val Leu Pro Asp Pro Lys Pro Gln Gly Pro Pro Val Ala Ser 355 360 365 Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro 370 375 380 Ala Gly Ala Val Phe Ile Leu Gly Thr Leu Leu Leu Trp Leu Cys Gln 385 390 395 400 Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro Ala Pro Pro Leu Pro Gly 405 410 415 His Arg Pro Pro Gly Thr Ala Arg Asp Arg Ser Gly Asp Lys Asp Leu 420 425 430 Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro Gly Val Gly Leu Cys Glu 435 440 445 Glu His Gly Ser Pro Ala Ala Pro Gln His Leu Leu Gly Pro Gly Pro 450 455 460 Val Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Ile His Thr 465 470 475 480 His Thr His Thr His Ser His Thr His Ser His Val Glu Gly Lys Val 485 490 495 His Gln His Ile His Tyr Gln Cys 500 <210> SEQ ID NO 20 <211> LENGTH: 342 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 20 Met Ala Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr 1 5 10 15 Val Arg Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met 20 25 30 Trp Thr Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg 35 40 45 Val Leu Pro Gln Gly Leu Lys Val Lys Glu Val Glu Ala Glu Asp Ala 50 55 60 Gly Val Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val 65 70 75 80 Asn Tyr Thr Leu Ile Ile Met Asp Asp Ile Ser Pro Gly Lys Glu Ser 85 90 95 Pro Gly Pro Gly Gly Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln 100 105 110 Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg 115 120 125 Val Ile Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala 130 135 140 Ser Gly His Pro Arg Pro Asp Ile Met Trp Met Lys Asp Asp Gln Thr 145 150 155 160 Leu Thr His Leu Glu Ala Ser Glu His Arg Lys Lys Lys Trp Thr Leu 165 170 175 Ser Leu Lys Asn Leu Lys Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg 180 185 190 Val Ser Asn Lys Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val 195 200 205 Ile Gln Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val 210 215 220 Asn Thr Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val 225 230 235 240 Arg Ser Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr 245 250 255 Gly Ser Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys 260 265 270 Phe Val Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser 275 280 285 Tyr Leu Asn Lys Leu Leu Ile Ser Arg Ala Arg Gln Asp Asp Ala Gly 290 295 300 Met Tyr Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser 305 310 315 320 Ala Phe Leu Thr Val Leu Pro Asp Pro Lys Pro Pro Gly Pro Pro Met 325 330 335 Ala Ser Ser Ser Ser Ser 340 <210> SEQ ID NO 21 <211> LENGTH: 1788 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: murine FGFR-L extracellular domain-Fc fusion polypeptide <221> NAME/KEY: CDS <222> LOCATION: (1)..(1782) <400> SEQUENCE: 21 atg acg cgg agc ccc gcg ctg ctg ctg ctg cta ttg ggg gcc ctc ccg 48 Met Thr Arg Ser Pro Ala Leu Leu Leu Leu Leu Leu Gly Ala Leu Pro 1 5 10 15 tcg gct gag gcg gcg cga gga ccc cca aga atg gca gac aaa gtg gtc 96 Ser Ala Glu Ala Ala Arg Gly Pro Pro Arg Met Ala Asp Lys Val Val 20 25 30 cca cgg cag gtg gcc cgc ctg ggc cgc act gtg cgg cta cag tgc cca 144 Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro 35 40 45 gtg gag ggg gac cca cca ccg ttg acc atg tgg acc aaa gat ggc cgc 192 Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg 50 55 60 aca atc cac agt ggc tgg agc cgc ttc cgt gtg ctg ccc cag ggt ctg 240 Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu 65 70 75 80 aag gtg aag gag gtg gag gcc gag gat gcc ggt gtt tat gtg tgc aag 288 Lys Val Lys Glu Val Glu Ala Glu Asp Ala Gly Val Tyr Val Cys Lys 85 90 95 gcc acc aat ggc ttt ggc agc ctc agc gtc aac tac act ctc atc atc 336 Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Ile Ile 100 105 110 atg gat gat att agt cca ggg aag gag agc cct ggg cca ggt ggt tct 384 Met Asp Asp Ile Ser Pro Gly Lys Glu Ser Pro Gly Pro Gly Gly Ser 115 120 125 tcg ggg ggc cag gag gac cca gcc agc cag cag tgg gca cgg cct cgc 432 Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg 130 135 140 ttc aca cag ccc tcc aag atg agg cgc cga gtg att gca cgg cct gtg 480 Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val 145 150 155 160 ggt agc tct gtg cgg ctc aag tgt gtg gcc agt ggg cac cca cgg cca 528 Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro 165 170 175 gac atc atg tgg atg aag gat gac cag acc ttg acg cat cta gag gct 576 Asp Ile Met Trp Met Lys Asp Asp Gln Thr Leu Thr His Leu Glu Ala 180 185 190 agt gaa cac aga aag aag aag tgg aca ctg agc ttg aag aac ctg aag 624 Ser Glu His Arg Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Lys 195 200 205 cct gaa gac agt ggc aag tac acg tgc cgt gta tct aac aag gcc ggt 672 Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser Asn Lys Ala Gly 210 215 220 gcc atc aac gcc acc tac aaa gtg gat gta atc cag cgg act cgt tcc 720 Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser 225 230 235 240 aag cct gtg ctc aca ggg aca cac cct gtg aac aca acg gtg gac ttc 768 Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe 245 250 255 ggt ggg aca acg tcc ttc cag tgc aag gtg cgc agt gac gtg aag cct 816 Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro 260 265 270 gtg atc cag tgg ctg aag cgg gtg gag tac ggc tcc gag gga cgc cac 864 Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ser Glu Gly Arg His 275 280 285 aac tcc acc att gat gtg ggt ggc cag aag ttt gtg gtg ttg ccc acg 912 Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr 290 295 300 ggt gat gtg tgg tca cgg cct gat ggc tcc tac ctc aac aag ctg ctc 960 Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu 305 310 315 320 atc tct cgg gcc cgc cag gat gat gct ggc atg tac atc tgc cta ggt 1008 Ile Ser Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly 325 330 335 gca aat acc atg ggc tac agt ttc cgt agc gcc ttc ctc act gta tta 1056 Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu 340 345 350 cca gac ccc aaa cct cca ggg cct cct atg gct tct tca tcg gtc gac 1104 Pro Asp Pro Lys Pro Pro Gly Pro Pro Met Ala Ser Ser Ser Val Asp 355 360 365 aaa act cac aca tgc cca ccg tgc cca gca cct gaa ctc ctg ggg gga 1152 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 370 375 380 ccg tca gtc ttc ctc ttc ccc cca aaa ccc aag gac acc ctc atg atc 1200 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 385 390 395 400 tcc cgg acc cct gag gtc aca tgc gtg gtg gtg gac gtg agc cac gaa 1248 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 405 410 415 gac cct gag gtc aag ttc aac tgg tac gtg gac ggc gtg gag gtg cat 1296 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 420 425 430 aat gcc aag aca aag ccg cgg gag gag cag tac aac agc acg tac cgt 1344 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 435 440 445 gtg gtc agc gtc ctc acc gtc ctg cac cag gac tgg ctg aat ggc aag 1392 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 450 455 460 gag tac aag tgc aag gtc tcc aac aaa gcc ctc cca gcc ccc atc gag 1440 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 465 470 475 480 aaa acc atc tcc aaa gcc aaa ggg cag ccc cga gaa cca cag gtg tac 1488 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 485 490 495 acc ctg ccc cca tcc cgg gat gag ctg acc aag aac cag gtc agc ctg 1536 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 500 505 510 acc tgc ctg gtc aaa ggc ttc tat ccc agc gac atc gcc gtg gag tgg 1584 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 515 520 525 gag agc aat ggg cag ccg gag aac aac tac aag acc acg cct ccc gtg 1632 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 530 535 540 ctg gac tcc gac ggc tcc ttc ttc ctc tac agc aag ctc acc gtg gac 1680 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 545 550 555 560 aag agc agg tgg cag cag ggg aac gtc ttc tca tgc tcc gtg atg cat 1728 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 565 570 575 gag gct ctg cac aac cac tac acg cag aag agc ctc tcc ctg tct ccg 1776 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 580 585 590 ggt aaa tgataa 1788 Gly Lys <210> SEQ ID NO 22 <211> LENGTH: 594 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: murine FGFR-L extracellular domain-Fc fusion polypeptide <400> SEQUENCE: 22 Met Thr Arg Ser Pro Ala Leu Leu Leu Leu Leu Leu Gly Ala Leu Pro 1 5 10 15 Ser Ala Glu Ala Ala Arg Gly Pro Pro Arg Met Ala Asp Lys Val Val 20 25 30 Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro 35 40 45 Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg 50 55 60 Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu 65 70 75 80 Lys Val Lys Glu Val Glu Ala Glu Asp Ala Gly Val Tyr Val Cys Lys 85 90 95 Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Ile Ile 100 105 110 Met Asp Asp Ile Ser Pro Gly Lys Glu Ser Pro Gly Pro Gly Gly Ser 115 120 125 Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg 130 135 140 Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val 145 150 155 160 Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro 165 170 175 Asp Ile Met Trp Met Lys Asp Asp Gln Thr Leu Thr His Leu Glu Ala 180 185 190 Ser Glu His Arg Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Lys 195 200 205 Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser Asn Lys Ala Gly 210 215 220 Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser 225 230 235 240 Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe 245 250 255 Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro 260 265 270 Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ser Glu Gly Arg His 275 280 285 Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr 290 295 300 Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu 305 310 315 320 Ile Ser Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly 325 330 335 Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu 340 345 350 Pro Asp Pro Lys Pro Pro Gly Pro Pro Met Ala Ser Ser Ser Val Asp 355 360 365 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 370 375 380 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 385 390 395 400 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 405 410 415 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 420 425 430 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 435 440 445 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 450 455 460 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 465 470 475 480 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 485 490 495 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 500 505 510 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 515 520 525 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 530 535 540 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 545 550 555 560 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 565 570 575 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 580 585 590 Gly Lys 

What is claimed is:
 1. An isolated nucleic acid molecule comprising: (a) the nucleotide sequence as set forth in SEQ ID NO: 4; (b) a nucleotide sequence encoding the polypeptide as set forth in SEQ ID NO: 5; (c) a nucleotide sequence which hybridizes under at least moderately stringent conditions to the complement of the nucleotide sequence of either (a) or (b), wherein the encoded polypeptide has an activity of the polypeptide as set forth in SEQ ID NO: 5; or (d) a nucleotide sequence complementary to the nucleotide sequence of any of (a)-(c).
 2. An isolated nucleic acid molecule comprising: (a) a nucleotide sequence encoding a polypeptide that is at least about 70 percent identical to the polypeptide as set forth in SEQ ID NO: 5, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5; (b) a nucleotide sequence encoding an allelic variant or splice variant of the nucleotide sequence as set forth in SEQ ID NO: 4, or the nucleotide sequence of (a); (c) a region of the nucleotide sequence of SEQ ID NO: 4, or the nucleotide sequence of either (a) or (b), encoding a polypeptide fragment of at least about 25 amino acid residues, wherein the polypeptide fragment has an activity of the encoded polypeptide as set forth in SEQ ID NO: 5, or is antigenic; (d) a region of the nucleotide sequence of SEQ ID NO: 4, or the nucleotide sequence of any of (a)-(c) comprising a fragment of at least about 16 nucleotides; (e) a nucleotide sequence that hybridizes under at least moderately stringent conditions to the complement of the nucleotide sequence of any of (a)-(d), wherein the encoded polypeptide has an activity of the polypeptide as set forth in SEQ ID NO: 5; or (f) a nucleotide sequence complementary to the nucleotide sequence of any of (a)-(e).
 3. An isolated nucleic acid molecule comprising: (a) a nucleotide sequence encoding a polypeptide as set forth in SEQ ID NO: 5 with at least one conservative amino acid substitution, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5; (b) a nucleotide sequence encoding a polypeptide as set forth in SEQ ID NO: 5 with at least one amino acid insertion, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5; (c) a nucleotide sequence encoding a polypeptide as set forth in SEQ ID NO: 5 with at least one amino acid deletion, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5; (d) a nucleotide sequence encoding a polypeptide as set forth in SEQ ID NO: 5 which has a C- and/or N-terminal truncation, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5; (e) a nucleotide sequence encoding a polypeptide as set forth in SEQ ID NO: 5 with at least one modification that is an amino acid substitution, amino acid insertion, amino acid deletion, C-terminal truncation, or N-terminal truncation, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5; (f) a nucleotide sequence of any of (a)-(e) comprising a fragment of at least about 16 nucleotides; (g) a nucleotide sequence that hybridizes under at least moderately stringent conditions to the complement of the nucleotide sequence of any of (a)-(f), wherein the encoded polypeptide has an activity of the polypeptide as set forth in SEQ ID NO: 5; or (h) a nucleotide sequence complementary to any of (a)-(g).
 4. A vector comprising the nucleic acid molecule of any of claims 1, 2, or
 3. 5. A host cell comprising the vector of claim
 4. 6. The host cell of claim 5 that is a eukaryotic cell.
 7. The host cell of claim 5 that is a prokaryotic cell.
 8. A process of producing an FGFR-L polypeptide comprising culturing the host cell of claim 5 under suitable conditions to express the polypeptide, and optionally isolating the polypeptide from the culture.
 9. The process of claim 8, wherein the nucleic acid molecule comprises promoter DNA other than the promoter DNA for the native FGFR-L polypeptide operatively linked to the DNA encoding the FGFR-L polypeptide.
 10. The isolated nucleic acid molecule according to claim 2, wherein the percent identity is determined using a computer program that is GAP, BLASTN, FASTA, BLASTA, BLASTX, BestFit, or the Smith-Waterman algorithm. 